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Genetics of Endocrine and Neuroendocrine Neoplasias (PDQ®)

Multiple Endocrine Neoplasia Type 2

Clinical Description

The endocrine disorders observed in multiple endocrine neoplasia type 2 (MEN2) are medullary thyroid cancer (MTC); its precursor, C-cell hyperplasia (CCH); pheochromocytoma; and parathyroid adenomas and/or hyperplasia. MEN2-associated MTC is often bilateral and/or multifocal and arises in the background of CCH. In contrast, sporadic MTC is typically unilateral and/or unifocal. Since approximately 75% to 80% of sporadic cases also have associated CCH, this histopathologic feature cannot be used as a predictor of familial disease.[1] Metastatic spread of MTC to regional lymph nodes (i.e., parathyroid, paratracheal, jugular chain, and upper mediastinum) or to distant sites, such as the liver, is common in patients who present with a palpable thyroid mass or diarrhea.[2,3] Although pheochromocytomas rarely metastasize, they can be clinically significant in cases of intractable hypertension or anesthesia-induced hypertensive crises. Parathyroid abnormalities in MEN2 can range from benign parathyroid adenomas or multigland hyperplasia to clinically evident hyperparathyroidism with hypercalcemia and renal stones.

Historically, individuals and families with MEN2 were classified into one of the following three clinical subtypes based on the presence or absence of certain endocrine tumors in the individual or family:

  1. MEN2A (OMIM).
  2. Familial medullary thyroid carcinoma (FMTC) (OMIM).
  3. MEN2B (OMIM).

Current stratification is moving away from a solely phenotype-based classification and more toward one that is based on genotype (i.e., the mutation) and phenotype.[4]

Clinical findings in the three MEN2 subtypes are summarized in Table 3. All three subtypes confer a high risk of MTC; MEN2A and MEN2B confer an increased risk of pheochromocytoma, and MEN2A has an increased risk of parathyroid hyperplasia and/or adenoma. Classifying a patient or family by MEN2 subtype is useful in determining prognosis and management.

Table 3. Percentage of Patients with Clinical Features of MEN2 by Subtype
SubtypeMedullary Thyroid Carcinoma (%)aPheochromocytoma (%)aParathyroid Disease (%)a
FMTC = familial medullary thyroid carcinoma; MEN2 = multiple endocrine neoplasia type 2.
aPercentages based on observations in referral populations.[5-9]
MEN2A955015–30
FMTC~10000
MEN2B10050Uncommon

MTC and CCH

MTC originates in calcitonin-producing cells (C-cells) of the thyroid gland. MTC is diagnosed when nests of C-cells extend beyond the basement membrane and infiltrate and destroy thyroid follicles. CCH is diagnosed histologically by the presence of an increased number of diffusely scattered or clustered C-cells.[10,11] Individuals with RET (REarranged during Transfection) mutations and CCH are at substantially increased risk of progressing to MTC, although such progression is not universal.[12,13] MTC and CCH are suspected in the presence of an elevated plasma calcitonin concentration.

A study of 10,864 patients with nodular thyroid disease found 44 (1 of every 250) cases of MTC after stimulation with calcitonin, none of which were clinically suspected. Consequently, half of these patients had no evidence of MTC on fine-needle biopsy and thus might not have undergone surgery without the positive calcitonin stimulation test.[14] CCH associated with a positive calcitonin stimulation test occurs in about 5% of the general population; therefore, the plasma calcitonin responses to stimulation do not always distinguish CCH from small MTC and cannot always distinguish between carriers and noncarriers in an MEN2 family.[12,13,15]

MTC accounts for 2% to 3% of new cases of thyroid cancer diagnosed annually in the United States,[16] although this figure may be an underrepresentation of true incidence because of changes in diagnostic techniques. The total number of new cases of MTC diagnosed annually in the United States is between 1,000 and 1,200, about 75% of which are sporadic (i.e., they occur in the absence of a family history of either MTC or other endocrine abnormalities seen in MEN2). The peak incidence of the sporadic form is in the fifth and sixth decades of life.[2,17] A study in the United Kingdom estimated the incidence of MTC at 20 to 25 new cases per year among a population of 55 million.[7]

In the absence of a positive family history, MEN2 may be suspected when MTC occurs at an early age or is bilateral or multifocal. While small series of apparently sporadic MTC cases have suggested a higher prevalence of germline RET mutations,[18,19] larger series indicate a prevalence range of 1% to 7%.[20,21] Based on these data, it is widely recommended that RET gene mutation testing be performed for all cases of MTC.[22-25]

Level of evidence (Screening): 3

Natural history of MTC

Thyroid cancer represents approximately 3% of new malignancies occurring annually in the United States, with an estimated 62,980 cancer diagnoses and 1,890 cancer deaths per year.[26] Of these cancer diagnoses, 2% to 3% are MTC.[16,27]

MTC arises from the parafollicular calcitonin-secreting cells of the thyroid gland. MTC occurs in sporadic and familial forms and may be preceded by CCH, although CCH is a relatively common abnormality in middle-aged adults.[10,11]

Average survival for MTC is lower than that for more common thyroid cancers (e.g., 83% 5-year survival for MTC compared with 90% to 94% 5-year survival for papillary and follicular thyroid cancer).[27,28] Survival is correlated with stage at diagnosis, and decreased survival in MTC can be accounted for in part by a high proportion of late-stage diagnosis.[27-29]

In addition to early stage at diagnosis, other factors associated with improved survival in MTC include smaller tumor size, younger age at diagnosis, familial versus sporadic form, and diagnosis by biochemical screening (i.e., screening for calcitonin elevation) versus symptoms.[29-32]

A Surveillance, Epidemiology, and End Results population-based study of 1,252 MTC patients found that survival varied by extent of local disease. For example, the 10-year survival rates ranged from 95.6% for those with disease confined to the thyroid gland to 40% for those with distant metastases.[30]

Hereditary MTC

While the majority of MTC cases are sporadic, approximately 20% to 25% are hereditary because of mutations in the RET proto-oncogene.[33-35] Mutations in the RET gene cause MEN2, an autosomal dominant disorder associated with a high lifetime risk of MTC. Multiple endocrine neoplasia type 1 (MEN1) (OMIM) is an autosomal dominant endocrinopathy that is genetically and clinically distinct from MEN2; however, the similar nomenclature for MEN1 and MEN2 may cause confusion. There is no increased risk of thyroid cancer for MEN1. (Refer to the MEN1 section of this summary for more information.)

Pheochromocytoma

Pheochromocytomas (OMIM) arise from the catecholamine-producing chromaffin cells of the adrenal medulla. They are a relatively rare tumor and are suspected among patients with refractory hypertension or when biochemical screening reveals elevated excretion of catecholamines and catecholamine metabolites (i.e., norepinephrine, epinephrine, metanephrine, and vanillylmandelic acid) in 24-hour urine collections or plasma. In the past, measurement of urinary catecholamines was considered the preferred biochemical screening method. However, given that catecholamines are only released intermittently and are metabolized in the adrenal medulla into metanephrine and normetanephrine, the measurement of urine or plasma fractionated metanephrines has become the gold standard.[36-41] When biochemical screening in an individual who has or is at risk of MEN2 suggests pheochromocytoma, localization studies, such as magnetic resonance imaging (MRI) or computed tomography, can be performed.[42] Confirmation of the diagnosis can be made using I131-metaiodobenzylguanidine scintigraphy or positron emission tomography imaging.[13,42-44]

A diagnosis of MEN2 is often considered in individuals with bilateral pheochromocytoma, those with an early age of onset (age <35 years), and those with a personal and/or family history of MTC or hyperparathyroidism. However, MEN2 is not the only genetic disorder that includes a predisposition to pheochromocytoma. Other disorders include neurofibromatosis type 1 (NF1), von Hippel-Lindau disease (VHL),[45] and the hereditary paraganglioma syndromes.[46] (Refer to the von Hippel-Lindau Syndrome section in the PDQ summary on the Genetics of Kidney Cancer for more information about VHL.) A large European consortium that included 271 patients from Germany,[47] 314 patients from France,[48] and 57 patients from Italy (total = 642) with apparently sporadic pheochromocytoma analyzed the known pheochromocytoma/functional paraganglioma susceptibility genes (NF1, RET, VHL, SDHB, and SDHD).[49] The diagnosis of NF1 in this series was made clinically, while all other conditions were diagnosed based on the presence of a germline mutation in the causative gene. The disease was associated with a positive family history in 166 (25.9%) patients; germline mutations were detected in RET (n = 31), VHL (n = 56), NF1 (n = 14), SDHB (n = 34), or SDHD (n = 31). Rigorous clinical evaluation and pedigree analysis either before or after testing revealed that of those with a positive family history and/or a syndromic presentation, 58.4% carried a mutation, compared with 12.7% who were nonsyndromic and/or had no family history. Of the 31 individuals with a germline RET mutation, 28 (90.3%) had a positive family history and/or syndromic presentation, suggesting that most individuals with RET mutations and pheochromocytoma will have a positive family history or other manifestations of the disease.

These data indicate that a significant proportion of individuals presenting with apparently sporadic pheochromocytoma are carriers of germline genetic mutations. Of those with apparently sporadic disease, up to 46% have a mutation in one of the susceptibility genes.[50] Studies have identified additional susceptibility genes that predispose to pheochromocytoma, including TMEM127, MAX, and SDHAF2.[51-54] Mutations in these genes are thought to account for a small proportion of all hereditary pheochromocytoma. Since testing for mutations in multiple genes in every patient may not be feasible or cost-effective, clinical and genetic screening algorithms have been proposed to assist clinicians in deciding which genes to test and in which order.[42,48,49,55-57]

Primary Hyperparathyroidism (PHPT)

PHPT is the third most common endocrine disorder in the general population. The incidence increases with age with the vast majority of cases occurring after the sixth decade of life. Approximately 80% of cases are the results of a single adenoma.[58] PHPT can also be seen as a component tumor in several different hereditary syndromes, including the following:

  • MEN1.
  • Hyperparathyroidism-Jaw Tumor syndrome.
  • Familial Isolated Hyperparathyroidism.
  • MEN2.[59-61]

Hereditary PHPT is typically multiglandular, presents earlier in life, and can have histologic evidence of both adenoma and glandular hyperplasia.

Clinical Diagnosis of MEN2 Subtypes

The diagnosis of the three MEN2 clinical subtypes relies on a combination of clinical findings, family history, and molecular genetic testing of the RET gene (chromosomal region 10q11.2).

MEN2A

MEN2A is diagnosed clinically by the occurrence of two or more specific endocrine tumors (MTC, pheochromocytoma, or parathyroid adenoma and/or hyperplasia) in a single individual or in close relatives.

The MEN2A subtype makes up about 60% to 90% of MEN2 cases. The MEN2A subtype was initially called Sipple syndrome.[62] Since genetic testing for RET mutations has become available, it has become apparent that about 95% of individuals with MEN2A will develop MTC; about 50% will develop pheochromocytoma; and about 15% to 30% will develop hyperparathyroidism.[13,63-65]

MTC is generally the first manifestation of MEN2A. In asymptomatic at-risk individuals, stimulation testing may reveal elevated plasma calcitonin levels and the presence of CCH or MTC.[13,64] In families with MEN2A, the biochemical manifestations of MTC generally appear between the ages of 5 and 25 years (mean 15 years).[13] If presymptomatic screening is not performed, MTC typically presents as a neck mass or neck pain at about age 5 to 20 years. More than 50% of such patients have cervical lymph node metastases.[2] Diarrhea, the most frequent systemic symptom, occurs in patients with a plasma calcitonin level of greater than 10 ng/mL and implies a poor prognosis.[2] Up to 30% of patients with MTC present with diarrhea and advanced disease.[66]

MEN2-associated pheochromocytomas are more often bilateral, multifocal, and associated with extratumoral medullary hyperplasia.[67-69] They also have an earlier age of onset and are less likely to be malignant than their sporadic counterparts.[67,70] MEN2-associated pheochromocytomas usually present after MTC, typically with intractable hypertension.[6]

Unlike the PHPT seen in MEN1, hyperparathyroidism in individuals with MEN2 is typically asymptomatic or associated with only mild elevations in calcium.[66,71] A series of 56 patients with MEN2-related hyperparathyroidism has been reported by the French Calcitonin Tumors Study Group.[71] The median age at diagnosis was 38 years, documenting that this disorder is rarely the first manifestation of MEN2. This is in sharp contrast to MEN1, in which the vast majority of patients (87%–99%) initially present with primary hyperparathyroidism.[72-74] Parathyroid abnormalities were found concomitantly with surgery for medullary thyroid carcinoma in 43 patients (77%). Two-thirds of the patients were asymptomatic. Among the 53 parathyroid glands removed surgically, there were 24 single adenomas, four double adenomas, and 25 hyperplastic glands.

A small number of families with MEN2A have pruritic skin lesions known as cutaneous lichen amyloidosis. This lichenoid skin lesion is located over the upper portion of the back and may appear before the onset of MTC.[75,76]

Figure 2 depicts some of the classic manifestations of MEN2A in a family.

Pedigree showing some of the classic features of a family with a deleterious RET mutation across four generations, including transmission occurring through paternal lineage. The unaffected female proband is shown as having an affected brother (medullary thyroid cancer diagnosed at age 22 y and hyperparathyroidism diagnosed at age 24 y), father (medullary thyroid cancer diagnosed at age 54 y and pheochromocytoma diagnosed at age 67 y), and paternal aunt (medullary thyroid cancer diagnosed at age 38 y).
Figure 2. MEN2A pedigree. This pedigree shows some of the classic features of a family with a deleterious RET mutation across four generations, including affected family members with medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism. Age at onset can vary widely, even within families. Medullary thyroid cancer can present with earlier onset and more aggressive disease in successive generations, depending on the genotype. MEN2A families may exhibit some or all of these features. As an autosomal dominant syndrome, transmission can occur through maternal or paternal lineages.

Familial medullary thyroid carcinoma (FMTC)

The FMTC subtype makes up 5% to 35% of MEN2 cases and is defined as families with four or more cases of MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia.[63] Families with two or three cases of MTC and incompletely documented screening for pheochromocytoma and parathyroid disease may actually represent MEN2A; it has been suggested that these families should be considered unclassified.[7,77] Misclassification of families with MEN2A as having FMTC (because of too-small family size or later onset of other manifestations of MEN2A) may result in overlooking the risk of pheochromocytoma, a disease with significant morbidity and mortality. For this reason, there is debate about whether FMTC represents a separate entity or is a variation of MEN2A in which there is a lack of or delay in the onset of the other (nonthyroidal) manifestations of the MEN2A syndrome.[78] Some authors recommended,[25] therefore, that patients thought to have pure FMTC also be screened for pheochromocytoma and hyperparathyroidism. (Refer to the Screening of at-risk individuals for pheochromocytoma and Screening of at-risk individuals for hyperparathyroidism sections of this summary for more information.)

MEN2B

MEN2B is diagnosed clinically by the presence of mucosal neuromas of the lips and tongue, medullated corneal nerve fibers, distinctive facies with enlarged lips, an asthenic Marfanoid body habitus, and MTC.[79-81]

The MEN2B subtype makes up about 5% of MEN2 cases. The MEN2B subtype was initially called mucosal neuroma syndrome or Wagenmann-Froboese syndrome.[82] MEN2B is characterized by the early development of an aggressive form of MTC in all patients.[82,83] Patients with MEN2B who do not undergo thyroidectomy at an early age (at approximately age 1 year) are likely to develop metastatic MTC at an early age. Before intervention with early risk-reducing thyroidectomy, the average age at death in patients with MEN2B was 21 years. Pheochromocytomas occur in about 50% of MEN2B cases; about half are multiple and often bilateral. Clinically apparent parathyroid disease is very uncommon.[5,63,84] Patients with MEN2B may be identified in infancy or early childhood by a distinctive facial appearance and the presence of mucosal neuromas on the anterior dorsal surface of the tongue, palate, or pharynx. The lips become prominent over time, and submucosal nodules may be present on the vermilion border of the lips. Neuromas of the eyelids may cause thickening and eversion of the upper eyelid margins. Prominent thickened corneal nerves may be seen by slit lamp examination.

About 40% of patients have diffuse ganglioneuromatosis of the gastrointestinal tract. Associated symptoms include abdominal distension, megacolon, constipation, and diarrhea. About 75% of patients have a Marfanoid habitus, often with kyphoscoliosis or lordosis, joint laxity, and decreased subcutaneous fat. Proximal muscle wasting and weakness can also be seen.[80,81]

Genetically Related Disorder

Hirschsprung disease (HSCR)

HSCR (OMIM), a disorder of the enteric plexus of the colon that typically results in enlargement of the bowel and constipation or obstipation in neonates, is observed in a small number of individuals with MEN2A, FMTC, or very rarely, MEN2B.[85] Up to 40% of familial cases of HSCR and 3% to 7% of sporadic cases are associated with germline mutations in the RET proto-oncogene and are designated HSCR1.[86,87] Some of these RET mutations are located in codons that lead to the development of MEN2A or FMTC (i.e., codons 609, 618, and 620).[85,88]

In a study of 44 families, seven families (16%) had cosegregation of MEN2A and HSCR1. The probability that individuals in a family with MEN2A and an exon 10 Cys mutation would manifest HSCR1 was estimated to be 6% in one series.[86] Furthermore, in a multicenter international RET mutation consortium study, 6 of 62 kindreds carrying either the C618R or C620R mutation also had HSCR.[63]

A novel analytic approach employing family-based association studies coupled with comparative and functional genomic analysis revealed that a common RET variant within a conserved enhancer-like sequence in intron 1 makes a 20-fold greater contribution to HSCR compared with all known RET mutations.[89] This mutation has low penetrance and different genetic effects in males and females. Transmission to sons and daughters leads to a 5.7-fold and 2.1-fold increase in susceptibility, respectively. This finding is consistent with the greater incidence of HSCR in males. Demonstrating this strong relationship between a common noncoding mutation in RET and the risk of HSCR also accounts for previous failures to detect coding mutations in RET-linked families.

Molecular Genetics of MEN2

MEN2 syndromes are the result of inherited mutations in the RET gene, located on chromosome region 10q11.2.[90-92] The RET gene is a proto-oncogene composed of 21 exons over 55 kilobase of genomic material.[93,94]

RET encodes a receptor tyrosine kinase with extracellular, transmembrane, and intracellular domains. Details of RET receptor and ligand interaction in this signaling pathway have been reviewed.[95] Briefly, the extracellular domain consists of a calcium-binding cadherin-like region and a cysteine-rich region that interacts with one of four ligands identified to date. These ligands, e.g., glial cell line–derived neurotrophic factor (GDNF), neurturin, persephin, and artemin, also interact with one of four coreceptors in the GDNF-family receptor–alpha family.[95] The tyrosine kinase catalytic core is located in the intracellular domain, which causes downstream signaling events through a variety of second messenger molecules. Normal tissues contain transcripts of several lengths.[96-98]

Genetic testing

MEN2 is a well-defined hereditary cancer syndrome for which genetic testing is considered an important part of the management for at-risk family members. It meets the criteria related to indications for genetic testing for cancer susceptibility outlined by the American Society of Clinical Oncology in its most recent genetic testing policy statement.[99] At-risk individuals are defined as first-degree relatives (parents, siblings, and children) of a person known to have MEN2. Testing allows the identification of people with asymptomatic MEN2 who can be offered risk-reducing thyroidectomy and biochemical screening as preventive measures. A negative mutation analysis in at-risk relatives, however, is informative only after a disease-causing mutation has been identified in an affected relative. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information.) Because early detection of at-risk individuals affects medical management, testing of children who have no symptoms is considered beneficial.[99,100] (Refer to the Genotype-Phenotype Correlations and Risk Stratification section of this summary for more information about clinical management of at-risk individuals.)

Germline DNA testing for RET mutations is generally recommended to all individuals with a diagnosis of MTC, regardless of whether there is a personal or family history suggestive of MEN2.[23,101] Approximately 95% of patients with MEN2A or MEN2B will have an identifiable germline RET mutation.[63] For FMTC the detection rate is slightly lower at 88%.[63] Importantly, 1% to 7% of apparently sporadic cases of MTC will carry a germline RET mutation, underscoring the importance of testing all cases.[18-21]

There is no evidence for the involvement of other genetic loci, and all mutation-negative families analyzed to date have demonstrated linkage to the RET gene. For families that do not have a detectable mutation, clinical recommendations can be based on the clinical features in the affected individual and in the family.

There is considerable diversity in the techniques used and the approach to RET mutation testing among the various laboratories that perform this procedure. Methods used to detect mutations in RET include polymerase chain reaction (PCR) followed by restriction enzyme digestion of PCR products, heteroduplex analysis, single-stranded conformation polymorphism analysis, denaturing high-performance liquid chromatography, and DNA sequencing.[102-105] Most testing laboratories, at a minimum, offer testing using a targeted exon approach; that is, the laboratories look for mutations in the exons that are most commonly found to carry mutations (exons 10, 11, 13, 14, 15 and 16). Other laboratories offer testing for all exons. If targeted exon testing in a family with a high clinical suspicion for MEN2 is normal, sequencing of the remaining exons can then be performed.

These differences in mutation detection method and targeted versus full gene testing represent important considerations for selecting a laboratory to perform a test and in interpreting the test result. (Refer to the PDQ summary on Cancer Genetics Risk Assessment and Counseling for more information about clinical validity.)

Genotype-Phenotype Correlations and Risk Stratification

Genotype-phenotype correlations in MEN2 are well-established and have long been used to guide clinicians in making medical management recommendations. Several groups have developed mutation-stratification tables based on clinical phenotype, age of onset, and aggressiveness of MTC.[23,25,77] This classification strategy was first put forth after the Seventh International Workshop on MEN in 2001, which provided guidelines for the age of genetic testing and prophylactic thyroidectomy.[23] This stratification was revised by the American Thyroid Association (ATA).[25] The original classification scheme provided three levels of risk based on the genetic mutation of an individual. The new guidelines by the ATA added a fourth category for codon 634 mutations, in recognition of their aggressive clinical course. The specific mutations and their ATA classification are summarized in Table 4 and Table 5 below. The ATA's classification scheme has not been prospectively validated as a basis for clinical decision-making.

ATA-level D mutations are the most aggressive and carry the highest risk of developing MTC.[25] These mutations, which are typically seen in MEN2B, are associated with the youngest age at disease onset and the highest risk of mortality. ATA-level C mutations (codon 634) are associated with a slightly lower risk, yet the MTC in patients with these mutations is still quite aggressive and may present at an early age. ATA-level A and level B mutations are associated with a lower risk of aggressive MTC relative to the risk seen in level C and level D mutation carriers. However, the risk of MTC is still substantially elevated over the general population risk and consideration of risk-reducing thyroidectomy is warranted.[25]

A European multicenter study of 207 RET mutation carriers supported previous suggestions that some mutations are associated with early-onset disease. For example, this study found that individuals with the C634Y mutation developed MTC at a significantly younger age (mean 3.2 years; 95% confidence interval [CI], 1.2–5.4) than individuals with the C634R mutation (mean 6.9 years; 95% CI, 4.9–8.8). In the former group of patients, risk-reducing thyroidectomy warrants consideration before the age of 5 years. Although limited by small numbers, the same study did not support a need for risk-reducing thyroidectomy in asymptomatic carriers of mutations in codons 609, 630, 768, 790, 791, 804, or 891 before the age of 10 years or for central lymph node dissection before the age of 20 years.[106] Some authors suggest using these differences as the basis for decisions on the timing of risk-reducing thyroidectomy and the extent of surgery.[23] Others have advocated using basal and stimulated calcitonin levels as a basis for determining the appropriate timing of thyroidectomy.[107]

Mutations 883 and 918 have been seen only in MEN2B and are associated with the earliest age of onset and the most aggressive form of MTC.[108-112] Approximately 95% of individuals with MEN2B will have the M918T mutation.[108-110,113] As discussed above, 50% of individuals with MEN2B will develop pheochromocytoma but PHPT is rare. In addition to mutations at codons 883 and 918, some individuals with a MEN2B-like phenotype have been found to carry two germline mutations.[114-118] It is likely that as testing for RET becomes more common in clinical practice, additional double mutation phenotypes will be described.

Mutations at codon 634 (ATA-level C) are by far the most frequent finding in families with MEN2A. One study of 477 RET carriers showed that 52.1% had the C634R mutation, 26.0% carried the C634Y mutation, and 9.1% had the C634G mutation.[63] In general, mutations at codon 634 are associated with pheochromocytomas and PHPT.[63,119] Until recently, MEN2A with cutaneous lichen amyloidosis had been seen almost exclusively in patients with mutations at codon 634.[63,65,120] However, a recent report described MTC and cutaneous lichen amyloidosis in an individual previously thought to have FMTC due to a codon 804 mutation.[121] Codon 634 mutations have also been described in FMTC but are almost exclusively C634Y.[63]

In summary, ATA-level D and level C mutations confer the highest risk of MTC (about 95% lifetime risk) with a more aggressive disease course. There is an increased risk of pheochromocytoma (up to 50%).[63,122] Individuals with codon 634 mutations (but not codon 883 or 918 mutations) also have an increased risk of PHPT.[63]

ATA-level B mutations, located in exon 10 of the RET gene, include mutations at codons 609, 611, 618, 620, and 630. These mutations involve cysteine residues in the extracellular domain of the RET protein and have been seen in families with MEN2A and those with MTC only (FMTC).[20,63,77,123-127] The risk of MTC in individuals with ATA-level B mutations is approximately 95% to 100%; the risk of pheochromocytoma and hyperparathyroidism is lower than that seen in ATA-level A mutations. In a large series of 518 probands with MTC undergoing RET testing, most individuals with codon 609, 611, 618, 620, or 630 mutations had only MTC and no other features suggestive of MEN2. The authors attributed this to the relatively short follow-up time, incomplete screening of family members, or the method of ascertainment (population-based).[33] Another large study of 390 exon 10 mutation carriers showed an age-related risk of pheochromocytoma for individuals carrying any exon 10 mutation of 23.1% by age 50 years and 33% by age 60 years. Overall prevalence of pheochromocytoma was 17%. This study reported a 3.9% risk of developing hyperparathyroidism by age 60 years.[128]

Individuals with ATA-level A mutations have a lower, albeit still elevated, lifetime risk of MTC. MTC associated with these mutations tends to follow a more indolent course and have a later age at onset, although there are several reports of individuals with ATA-level A mutations who developed MTC before age 20 years.[63,129-133] Although pheochromocytoma and PHPT are not commonly associated with level A mutations, they have been described.[133]

Table 4. Genotype-Phenotype Correlations and American Thyroid Association (ATA) Risk Levelsa,b
MutationATA Risk LevelMedullary Thyroid CancerPrimary HyperparathyroidismPheochromocytomaReferences
MA = majority (>50%); MI = minority (10%–50%); R = rare (<10%).
aRefer to Table 5 for more information about the ATA risk levels.
bAdapted from Kloos et al.[25]
cAssociated with multiple endocrine neoplasia type 2 mutations.
dAssociated with mutations based on limited families/case reports and may represent variants of unknown significance.
R321GcAMA  [134]
A510V Unknown  [135]
E511Kc Unknown  [135]
531/9 base pair duplicationAMA  [136]
532 duplicationcAUnknown  [137]
C515ScAMA  [138]
C531Rc MA  [135]
G533CAMA R[139-143]
R600QcAMI  [144]
K603EcAMI  [145]
Y606CcAUnknown  [146,147]
C609F/R/G/S/YBMAMIR/MI[34,63,122,128,148-152]
C611R/G/F/S/W/YBMAMIR/MI[63,122,128]
C618R/G/F/S/YBMAMIMI[63,122,128,153-156]
C620R/G/F/S/W/YBMAMIMI[63,122,128,149,155]
C630R/F/S/YBMARR[116,157]
D631YBMIRMA[158-160]
633/9 base pair duplicationBMAMI [161]
C634RCMAMIMA[63,122,162,163]
C634G/F/S/W/YCMAMIMA[63,122,155,162-164]
C634Y/Y791F MARMA[165]
634/12 base pair duplicationBMAMI [166]
635/insertion ELCR;T636PAMA  [146]
S649LAMIR [34,167-169]
K666E/NcAMI MI[135,146,170]
S686Nc MI  [155]
E768DAMARR[63,116,158,171]
R770Qc Unknown  [172]
N777ScAMI  [173]
L790FAMARR/MI[158,174,175]
Y791FAMAMIMI[158,174,176]
V804LAMAMIR[63,174,177]
V804MAMARR[63,174,177-179]
V804M+V778IcBMA  [180]
V804M+E805KdDMA MA[114]
V804M+Y806KdDMA MA[115-117]
V804M+S904Cc,dDMAMI [118]
G819KcAUnknown  [34]
R833CcAUnknown  [181]
R844QcAUnknown  [34,158]
L881Vc Unknown  [172]
A883FdDMA MA[111,112,182]
R886WcAMA  [183]
S891AAMAMIR[34,184-187]
R912PAMIMI [34,188]
M918TdDMA MA[63,155,189]

In addition to the mutations categorized in Table 4, a number of rare or novel RET mutations have been described. Some of these represent mutations that lead to an FMTC or MEN2 phenotype. Others may represent low penetrance alleles or modifying alleles that confer only a modest risk of developing MTC. Still others may be benign polymorphisms of no clinical significance. A variety of approaches, including segregation analyses, in silico analyses, association studies, and functional assays, can be employed to determine the functional and clinical significance of a given genetic variant. A publicly available RET mutation online database repository was recently developed and includes a complete list of mutations and their associated pathogenicity, phenotype, and other associated clinical information and literature references.[190]

Interventions

Risk-reducing thyroidectomy

Risk-reducing thyroidectomy and parathyroidectomy with reimplantation of one or more parathyroid glands into the neck or nondominant forearm is a preventive option for all subtypes of MEN2. To implement this management strategy, biochemical screening to identify CCH and/or genetic testing to identify persons who carry causative RET mutations is needed to identify candidates for risk-reducing surgery (see below). The optimal timing of surgery, however, is controversial.[3] Current recommendations are based on clinical experience and vary for different MEN2 subtypes, as noted in Table 5.

In contrast, a prospective analysis of 84 carriers of the RET gene mutation found that basal and pentagastrin-stimulated calcitonin levels could be used to determine the timing of total thyroidectomy.[107] When the basal or stimulated calcitonin was greater than 10 pg/mL, total thyroidectomy and central neck dissection were strongly recommended. In this series, a basal calcitonin level lower than 60 pg/mL was always associated with an intrathyroidal MTC; none of the 56 patients who went to surgery had metastatic involvement. These findings suggest that surgery can be safely delayed in gene carriers of a RET mutation until basal or stimulated calcitonin is above 10 pg/mL, while still maintaining the ability to achieve a disease-free state (i.e., an undetectable basal and stimulated calcitonin 6–12 months after surgery). The benefits of this approach are particularly noteworthy in the younger population of gene carriers, as a delay in surgery until the patient is older may reduce the risk of surgical complications. While this approach is promising, pentagastrin is currently not available in the United States for stimulation testing. Although calcium may be used as a substitute for pentagastrin, it has not been widely validated.

A smaller study has confirmed that calcitonin levels could be a useful approach to determine the timing of thyroidectomy.[191] This study utilized preoperative basal calcitonin levels and ultrasound findings to determine timing of prophylactic thyroidectomy in 24 RET mutation carriers, many of whom carried mutations in the highest risk level and had delayed surgery until after age 20 years. All 17 individuals who underwent surgery had elevated preoperative calcitonin levels on the fully-automated chemiluminescence immunoassay. Fifteen of 17 individuals had MTC, but only two had lymph node involvement and/or local tissue invasion, and 16 of 17 were disease free at 22 months. Two patients had CCH. Of note, only 6 of 15 individuals with MTC had elevated calcitonin levels using the radioimmunoassay. The study is limited by a small population of patients with low disease burden but suggests that some calcitonin assays may be more sensitive than others.

Table 5. American Thyroid Association Medullary Thyroid Cancer Risk Stratification and Management Guidelinesa
Risk levelMutated Codon(s)Age of RET TestingTiming of Prophylactic Thyroidectomy
aAdapted from Kloos et al.[25]
bThese mutations had not been reported at the time of the 7th International Workshop.[23]
cCriteria include a normal annual basal and/or stimulated serum count, normal annual neck ultrasound, less aggressive medullary thyroid cancer family history, and family preference.
D883, 918, and compound heterozygotes V804M+E805K, V804M+Y806C, and V804M+S904CASAP and within the first y of lifeASAP and within the first y of life.
C634<3–5 yBefore age 5 y.
B609b, 611, 618, 620, 630b, and compound heterozygote V804M+V778I<3–5 yConsider surgery before age 5 y. May delay surgery after age 5 y if criteria are met.c
A768, 790, 791, 804, 891<3–5 yMay delay surgery after age 5 y if criteria are met.c

In a study of biochemical screening in a large family with MEN2A performed before mutation analysis became available, 22 family members without evidence of clinical disease had elevated calcitonin and underwent thyroidectomy. During a mean follow-up period of 11 years, all remained free of clinical disease, and 3 out of 22 had transient elevation of postoperative calcitonin levels.[9] The use of biochemical screening is limited, however, by the lack of data on age-specific calcitonin levels in children younger than 3 years; caution should be used when interpreting these values in this age group.[25]

A study of 93 patients with MEN2 from a Dutch tumor registry documented the importance of early prophylactic thyroidectomy.[192] This group of patients represented all known Dutch patients with hereditary MTC; the majority of cases (67%) were codon 634 mutations; only 6% were MEN2B cases. Patients in this series were screened with either biochemical testing (pre-RET era) or RET mutation analysis. In both groups, patients underwent surgery at a later age than recommended by current guidelines (see Table 5), but the percentage from the pre-RET era was significantly higher (96% vs. 69%, P = .004). Older age at prophylactic thyroidectomy was significantly associated with a higher risk of postoperative persistent/recurrent disease. Although there is concern that young age at total thyroidectomy is associated with higher risk of surgical complications, this study found no such evidence.

Two additional case series provide further data supporting early risk-reducing thyroidectomy following testing for RET mutations.[193,194] Cases reported in both series could reflect selection biases: one study reported 71 patients from a national registry who had been treated with thyroidectomy but did not specify how these patients were selected, whereas the other study reported 21 patients seen at a referral center.[193,194] In both studies, a series of children from families with MEN2 or FMTC who were found to have RET mutations were screened for CCH and treated with risk-reducing thyroidectomy. These studies documented MTC in 93% of patients with MEN2 and 77% of patients with FMTC. The larger study found a correlation between age and larger tumor size, nodal metastases, postoperative recurrence of disease, and mean basal calcitonin levels. Surgical complications were rare.[193] No studies have compared the outcome of thyroidectomy based on mutation testing with thyroidectomy based on biochemical screening.

In one large series, 260 MEN2A subjects aged 0 to 20 years were identified as having undergone either an early total thyroidectomy (ages 1–5 years, n = 42), or late thyroidectomy (ages 6–20 years, n = 218).[195] There was a significantly lower rate of invasive or metastatic MTC among those who underwent surgery at an early age (57%) than among those who underwent surgery at a late age (76%). Follow-up information was available on only 28% of the cohort, as a result of the limitations of study design, with a median follow-up of only 2 years for this nonsystematically selected subgroup. Persistent or recurrent disease was reported among 0 of 9 early-surgery subjects, versus 21 of 65 late-surgery subjects. Both findings are consistent with the hypothesis that patients undergoing surgery before age 6 years have a more favorable outcome, but the nature of the data prevents this from being a definitive conclusion. Finally, there was evidence to suggest that subjects carrying codon 634 mutations were much more likely to present with invasive or metastatic MTC and to develop persistent or recurrent disease compared with those harboring mutations in codons 804, 618, or 620.

A study of young, clinically asymptomatic individuals with MEN2A sought to determine if early thyroidectomy could prevent or cure MTC.[196] This study included 50 consecutively identified RET mutation carriers who underwent thyroidectomy at 19 years or younger. Preoperative screening for CCH included basal and stimulated calcitonin levels and postoperative follow-up consisted of annual physical exam and intermittent basal and stimulated calcitonin measurements. All 50 individuals had at least 5 years of follow-up. Although MTC was identified in 33 of 50 patients at the time of surgery, in 44 of 50 (88%) there was no evidence of persistent or recurrent disease at a mean of 7 years follow-up. Six patients had basal or stimulated calcitonin abnormalities thought to represent residual MTC. None of the 22 patients operated on prior to age 8 years had any evidence of MTC. The data suggested that there was a lower incidence of persistent or recurrent disease in patients who had thyroidectomy earlier in life (defined as younger than 8 years) and who had no evidence of lymph node metastases.

Normal preoperative basal calcitonin does not exclude the possibility of the patient having MTC. In one study of 80 RET mutation carriers, 14 carriers had normal calcitonin tests and eight of these patients had small foci of MTC discovered at thyroidectomy.[13] Another study confirmed these findings,[82] as 14 children had total thyroidectomy based on positive genetic testing for MEN2; MTC was present in 11 and only four had elevated stimulated calcitonin levels prior to surgery. Although basal calcitonin levels may not be able to identify all patients with MTC preoperatively, this test has utility as a predictor of postoperative remission, lymph node metastases, and distant metastases.[197] In one study of 224 patients from a single institution, preoperative basal calcitonin levels greater than 500 pg/mL predicted failure to achieve biochemical remission.[197] The authors of this study found that nodal metastases started appearing at basal calcitonin levels of 40 pg/mL (normal, <10 pg/mL). In node-positive patients, distant metastases emerged at basal calcitonin levels of 150 pg/mL to 400 pg/mL. Using current sensitive calcitonin assays, a study of 308 RET carriers found that a normal basal preoperative calcitonin excluded the presence of lymph node metastases (100% negative predictive value).[198] Therefore, the preoperative basal calcitonin level is a useful prognostic indicator and may help guide the surgical approach.

While thyroidectomy prior to biochemical evidence of disease (normal preoperative calcitonin) may reduce the risk of recurrent disease, continued monitoring for residual or recurrent MTC is still recommended.[25,199] One study found that 10% of patients with MEN2A undergoing thyroidectomy developed recurrent disease, based on an initially undetectable basal and stimulated calcitonin levels (<2 pg/mL) that became positive 5 to 10 years after surgery.[196] Only 2% of patients had residual disease after prophylactic surgery as assessed by a persistently elevated basal or stimulated calcitonin.[196]

Questions remain concerning the natural history of MEN2. As more information is acquired, recommendations regarding the optimal age for thyroidectomy and the potential role for genetics and biochemical screening may change. For example, a case report documents MTC before age 5 years in two siblings with MEN2A.[200] Conversely, another case report documents onset of cancer in midlife or later in some families with FMTC and in elderly relatives who carry the FMTC genotype but have not developed cancer.[201] The possibility that certain mutations (e.g., Cys634) might convey a significantly worse prognosis, if confirmed, may permit tailoring intervention based on knowing the specific RET mutation.[195] These clinical observations suggest that the natural history of the MEN2 syndromes is variable and could be subject to modifying effects related to specific RET mutations, other genes, behavioral factors, or environmental exposures.

Level of evidence: 5

Screening of at-risk individuals for pheochromocytoma

The presence of a functioning pheochromocytoma should be excluded by appropriate biochemical screening before thyroidectomy in any patient with MEN2A or MEN2B. However, childhood pheochromocytomas are rare in MEN2.[25] The ATA has recommended that annual screening for pheochromocytoma be considered after the age of 8 years in patients with RET mutations in codons 630 and 634 and in patients with RET mutations associated with MEN2B.[25] In carriers of other MEN2A RET mutations, ATA recommends that annual screening begin by age 20 years. Patients with RET mutations associated only with FMTC should have periodic screening for pheochromocytoma beginning at age 20 years.[25] MRI or other imaging tests should be ordered only if the biochemical results are abnormal.[29,202] Studies of individuals with sporadic or hereditary pheochromocytoma (including, but not limited to, individuals with MEN2) have suggested that measurement of catecholamine metabolites, specifically plasma-free metanephrines and/or urinary fractionated metanephrines, provides a higher diagnostic sensitivity than urinary catecholamines because of the episodic nature of catecholamine excretion.[36-42,203] Several reviews provide a succinct summary of the biochemical diagnosis, localization, and management of pheochromocytoma.[42,204] In addition to surgery, there are other clinical situations in which patients with catecholamine excess face special risk. An example is the healthy at-risk female patient who becomes pregnant. Pregnancy, labor, or delivery may precipitate a hypertensive crisis in persons who carry an unrecognized pheochromocytoma. Pregnant patients who are found to have catecholamine excess require appropriate pharmacotherapy before delivery.

Level of evidence: 5

Screening of at-risk individuals for hyperparathyroidism

MEN2-related hyperparathyroidism is generally associated with mild, often asymptomatic hypercalcemia early in the natural history of the disease, which, if left untreated, may become symptomatic.[71] Childhood hyperparathyroidism is rare in MEN2. Three studies found the median age at diagnosis was about 38 years.[71,205,206] The ATA provides recommendations for annual screening for hyperparathyroidism.[25] Annual screening should begin at age 8 years in carriers of mutations in codons 630 and 634 and at age 20 years for carriers of other MEN2A RET mutations. Patients with mutations associated only with FMTC should have periodic testing after the age of 20 years. Testing should include albumin-corrected calcium or ionized serum calcium with or without intact parathyroid hormone (PTH) measurement.

Level of evidence: 5

Screening of at-risk individuals in kindreds without an identifiable RET mutation

MEN2A: Risk-reducing thyroidectomy is not routinely offered to at-risk individuals if the disorder is unconfirmed. The screening protocol for MTC is an annual calcitonin stimulation test; however, caution must be used in interpreting test results because CCH that is not a precursor to MTC occurs in about 5% of the population.[12,13,207] In addition, there is significant risk of false-negative test results in patients younger than 15 years.[13] Screening for pheochromocytoma and parathyroid disease is the same as described above.

FMTC: Annual screening for MTC, as for MEN2A.

Level of evidence: 5

Treatment for those with MTC

Standard treatment for adults with MTC is surgical removal of the entire thyroid gland, including the posterior capsule, and central lymph node dissection. Children with MEN2B having prophylactic thyroidectomy within the first year of life may not require central neck dissection unless there is radiological evidence of nodal disease.[25] Likewise, children with MEN2A or FMTC having prophylactic thyroidectomy before age 3 to 5 years should not have a central neck dissection in the absence of radiological evidence of metastatic lymph node involvement. The ATA also recommends that MEN2A and FMTC patients older than 5 years or asymptomatic MEN2B patients older than 1 year have a preoperative basal calcitonin test and neck ultrasound. A basal calcitonin level over 40 pg/mL or thyroid nodules greater than or equal to 5 mm requires further evaluation, as the patient may have more extensive disease requiring nodal dissection. If an MEN2B patient older than 1 year has nodules smaller than 5 mm or basal calcitonin lower than 40 pg/mL, then total thyroidectomy may be sufficient therapy, but the ATA task force favors prophylactic central neck dissection without lateral compartment dissection in the absence of radiographic evidence of metastatic involvement (level C recommendation).[25] See Table 6 for complete details.

Table 6. American Thyroid Association Management Guidelines for MEN2A/FMTC and MEN2Ba
SyndromeAge (y)Nodal DiseaseBasal Calcitonin (pg/mL)bNodule ≥ 5mmLymph Node DissectionStrength of Recommendationc
FMTC = familial medullary thyroid carcinoma; MEN2 = multiple endocrine neoplasia type 2.
aAdapted from Kloos et al.[25]
bBasal calcitonin values are applicable in patients older than 6 months.
cBased on grading definitions established by the U.S. Preventive Services Task Force.
MEN2A/FMTC<3–5No<40NoNoE
MEN2A/FMTC<3–5Yes>40YesYesB
MEN2A/FMTC>5No<40NoNoE
MEN2A/FMTC>5Yes>40YesYesB
MEN2B<1No<40NoNoE
MEN2B<1Yes>40YesYesB
MEN2B<1No<40NoYesC

The ATA recommends lymph node dissection for patients meeting any one of the following criteria:[25]

  • Radiographic evidence of nodal disease.
  • Basal calcitonin level greater than 40 pg/mL.
  • A thyroid nodule 5 mm or larger.

Patients who have had total thyroidectomy will require lifelong thyroid hormone replacement therapy. The dosing of medication is age-dependent and treatment should be initiated based on ideal body weight. For healthy adults 60 years and younger with no cardiac disease, a reasonable starting dose is 1.6 to 1.8 µg/kg given once daily.[208] Older patients may require 20% to 30% less thyroid hormone.[209] Children clear T4 more rapidly than adults and consequently require relatively higher replacement by body weight. Depending on the age of the child, replacement should be between 2 to 6 µg/kg.[210] It is important to note, however, that patients should be given replacement, rather than suppressive therapy. Since C-cell tumors are not thyroid-stimulating hormone (TSH)-dependent for growth, the T4 therapy for MTC patients therefore should be adjusted to maintain a TSH within the normal reference range.

There is no difference in survival between familial and sporadic forms of MTC when adjusted for clinicopathologic factors. Chemotherapy and radiation are not effective against this type of cancer,[3,211,212] although clinical trials (phases I–III) of various targeted molecular therapies are ongoing at selected centers. Some of these compounds have shown partial responses in a small percentage of patients, but most studies have demonstrated disease stability as the most favorable response.[213-216] The use of vandetanib and cabozantinib is approved by the U.S. Food and Drug Administration for adult patients with progressive metastatic MTC who are ineligible for surgery. A phase III study found that progression-free survival was longer in adults who received vandetanib than in those who received placebo.[217] There was no demonstration of improved overall survival, however. A phase I/II study of children with MEN2B found an objective partial response rate of 47% with vandetanib.[218]Future studies will likely focus on the development of new targeted therapies and the use of combination therapy in MTC. (Refer to NCI's List of Clinical Trials for more information about these trials. Refer to the PDQ summary on Thyroid Cancer Treatment for more information about the treatment of thyroid cancer.)

Level of evidence: 5

Treatment for those with pheochromocytoma

Pheochromocytoma may be either unilateral or bilateral in patients with MEN2. Laparoscopic adrenalectomy is the recommended approach by some authorities for the treatment of unilateral pheochromocytoma.[23,25] Two studies examined the value of a posterior retroperitoneoscopic adrenalectomy and found that it was safe and effective, with zero mortality, associated with a low rate of minor complications, and required conversion to open or laparoscopic lateral surgery in only 1.7%.[219,220] This approach appears to be a feasible and safe alternative to open or laparoscopic surgery, but extensive experience is needed.

In one series, 23 patients with a unilateral pheochromocytoma and a macroscopically normal contralateral adrenal gland were treated initially with unilateral adrenalectomy.[221] A pheochromocytoma developed within the retained gland in 12 (52%) of these subjects, occurring a mean of 11.9 years after initial surgery. During follow-up subsequent to unilateral adrenalectomy, no patient experienced a hypertensive crisis or other problems attributable to an undiagnosed pheochromocytoma. In contrast, 10 of 43 patients (23%) treated with bilateral adrenalectomy experienced at least one episode of acute adrenal insufficiency; one of these patients died. Unilateral adrenalectomy appears to represent a reasonable management strategy for unilateral pheochromocytoma in patients with MEN2,[222-224] when coupled with periodic surveillance (serum or urinary catecholamine measurements) for the development of disease in the contralateral adrenal gland.

Synchronous or metachronous bilateral disease is quite common in hereditary pheochromocytoma. In one retrospective series that spanned almost 50 years, 96 patients underwent surgical resection for hereditary pheochromocytoma.[225] Forty-seven patients had bilateral pheochromocytoma and 49 had unilateral pheochromocytoma at presentation. Open and laparoscopic approaches were used, and the extent of initial resection varied. Of the 49 patients who presented with a unilateral pheochromocytoma and who underwent unilateral total adrenalectomy, 15 (30%) developed pheochromocytoma in the contralateral gland. This occurred at a median of 8.2 years (range, 1 to 20 years) after initial diagnosis. Of the 15 patients who developed pheochromocytoma in the contralateral gland, 8 had MEN2A, 2 had MEN2B, 2 had VHL, and 1 had familial pheochromocytoma. The risk of contralateral tumor development increased over time, with 25% of patients developing tumors after a median of 6 years and 43% after a median of 32 years.

This study also analyzed whether cortical-sparing adrenalectomy is a feasible option for patients with bilateral pheochromocytomas or only one viable adrenal gland.[225] Cortical-sparing surgery is an attractive option because it minimizes the risk of adrenal insufficiency and the need for lifelong steroid supplementation. In this same series of 96 patients, 50 underwent cortical-sparing surgery. Twenty-eight of the cortical-sparing surgeries were part of an initial bilateral procedure, 11 were for unilateral disease, and 11 were part of a subsequent procedure on the contralateral gland. There was a 7% recurrence rate after cortical-sparing surgery versus a 3% recurrence rate after total resection (recurrence in the adrenal bed). Interestingly, the rate of recurrence was significantly higher in patients who underwent a laparoscopic procedure (14%) than in patients who underwent an open procedure (6%). The rate of recurrence was also significantly higher in patients who underwent a laparoscopic total adrenalectomy versus an open procedure. The frequency of adrenal insufficiency was lower in patients who underwent cortical-sparing surgery. One of 39 patients (3%) developed adrenal insufficiency after a cortical-sparing procedure; 5 of 25 patients (20%) developed adrenal insufficiency after total adrenalectomy. In summary, cortical-sparing surgery is a viable option for patients with hereditary pheochromocytoma, but ongoing surveillance for new or recurrent disease is necessary, especially in patients who undergo a laparoscopic procedure.

Level of evidence: 4

Treatment for those with hyperparathyroidism

Most patients with MEN2-related parathyroid disease are either asymptomatic or diagnosed incidentally at the time of thyroidectomy. Typically, the hypercalcemia (when present) is mild, although it may be associated with increased urinary excretion of calcium and nephrolithiasis. As a consequence, the indications for surgical intervention are generally similar to those recommended for patients with sporadic, primary hyperparathyroidism.[23] In general, fewer than four of the parathyroid glands are involved at the time of detected abnormalities in calcium metabolism.

Cure of hyperparathyroidism was achieved surgically in 89% of one large series of patients;[71] however, 22% of resected patients in this study developed postoperative hypoparathyroidism. Five patients (9%) had recurrent hyperparathyroidism. This series employed various surgical techniques, including total parathyroidectomy with autotransplantation to the nondominant forearm, subtotal parathyroidectomy, and resection only of glands that were macroscopically enlarged. Postoperative hypoparathyroidism developed in 4 of 11 patients (36%), 6 of 12 patients (50%), and 3 of 29 patients (10%), respectively. These data indicate that excision of only those parathyroid glands that are enlarged appears to be sufficient in most cases.

Some investigators have suggested using the MEN2 subtype to decide where to place the parathyroid glands that are identified at the time of thyroid surgery. For patients with MEN2B in whom the risk of parathyroid disease is quite low, the parathyroid glands may be left in the neck. For patients with MEN2A and FMTC, it is suggested that the glands be implanted in the nondominant forearm to minimize the need for further surgery on the neck after risk-reducing thyroidectomy and a central lymph node dissection.[226]

All patients who have undergone parathyroid surgery with autotransplantation of parathyroid tissue should be monitored for hypoparathyroidism.[25,227,228]

Medical therapy of hyperparathyroidism has gained popularity with the advent of calcimimetics, agents that sensitize the calcium-sensing receptors on the parathyroid glands to circulating calcium levels and thereby reduce circulating PTH levels. In a randomized, double-blind, placebo-controlled trial, cinacalcet hydrochloride was shown to induce sustained reduction in circulating calcium and PTH levels in patients with primary hyperparathyroidism.[229] In patients who are high-risk surgical candidates, those with recurrent hyperparathyroidism, or those in whom life expectancy is limited, medical therapy may be a viable alternative to a surgical approach.

Level of evidence: 5

Genetic Counseling

Mode of inheritance

All of the MEN2 subtypes are inherited in an autosomal dominant manner. For the child of someone with MEN2, the risk of inheriting the MEN2 mutation is 50%. Some individuals with MEN2, however, carry a de novo gene mutation; that is, they carry a new mutation that was not present in previous generations of their family and thus do not have an affected parent. The proportion of individuals with MEN2 who have an affected parent varies by subtype.

MEN2A: About 95% of affected individuals have an affected parent. It is appropriate to evaluate the parents of an individual with MEN2A for manifestations of the disorder. In the 5% of cases that are not familial, either de novo gene mutations or incomplete penetrance of the mutant allele is possible.[230]

FMTC: Multiple family members are affected; therefore, all affected individuals inherited the mutant gene from a parent.

MEN2B: About 50% of affected individuals have de novo RET gene mutations, and 50% have inherited the mutation from a parent.[231,232] The majority of de novo mutations are paternal in origin, but cases of maternal origin have been reported.[233]

Siblings of a proband: The risk to siblings depends on the genetic status of the parent, which can be clarified by pedigree analysis and/or DNA-based testing. In situations of apparent de novo gene mutations, germline mosaicism in an apparently unaffected parent must be considered, even though such an occurrence has not yet been reported.

Psychosocial issues

The psychosocial impact of genetic testing for mutations in RET has not been extensively studied. Published studies have had limitations such as small sample size and heterogeneous populations; thus, the clinical relevance of these findings should be interpreted with caution. Identification as the carrier of a deleterious mutation may affect self-esteem, family relationships, and quality of life.[234] In addition, misconceptions about genetic disease may result in familial blame and guilt.[235,236] Several review articles outline both the medical and psychological issues, especially those related to the testing of children.[237-240] The medical value of early screening and risk-reducing treatment are contrasted with the loss of decision-making autonomy for the individual. Lack of agreement between parents about the value and timing of genetic testing and surgery may spur the development of emotional problems within the family.

One study examined levels of psychological distress in the interval between submitting a blood sample and receiving genetic test results. Those individuals who experienced the highest level of distress were younger than 25 years, single, and had a history of responding to distressful situations with anxiety.[241] Mutation-positive parents whose children received negative test results did not seem to be reassured, questioned the reliability of the DNA test, and were eager to continue screening of their noncarrier children.[242]

A small qualitative study (N = 21) evaluated how patients with MEN2A and family members conceptualized participation in lifelong high-risk surveillance.[243] Ongoing surveillance was viewed as a reminder of a health threat. Acceptance and incorporation of lifelong surveillance into routine health care was essential for coping with the implications of this condition. Concern about genetic predisposition to cancer was peripheral to concerns about surveillance. Supportive interventions, such as Internet discussion forums, can serve as an ongoing means of addressing informational and support needs of patients with MTC undergoing lifelong surveillance.[244]

References

  1. Kaserer K, Scheuba C, Neuhold N, et al.: Sporadic versus familial medullary thyroid microcarcinoma: a histopathologic study of 50 consecutive patients. Am J Surg Pathol 25 (10): 1245-51, 2001. [PUBMED Abstract]
  2. Robbins J, Merino MJ, Boice JD Jr, et al.: Thyroid cancer: a lethal endocrine neoplasm. Ann Intern Med 115 (2): 133-47, 1991. [PUBMED Abstract]
  3. Moley JF, Debenedetti MK, Dilley WG, et al.: Surgical management of patients with persistent or recurrent medullary thyroid cancer. J Intern Med 243 (6): 521-6, 1998. [PUBMED Abstract]
  4. Machens A, Lorenz K, Dralle H: Constitutive RET tyrosine kinase activation in hereditary medullary thyroid cancer: clinical opportunities. J Intern Med 266 (1): 114-25, 2009. [PUBMED Abstract]
  5. Eng C: Seminars in medicine of the Beth Israel Hospital, Boston. The RET proto-oncogene in multiple endocrine neoplasia type 2 and Hirschsprung's disease. N Engl J Med 335 (13): 943-51, 1996. [PUBMED Abstract]
  6. Conte-Devolx B, Schuffenecker I, Niccoli P, et al.: Multiple endocrine neoplasia type 2: management of patients and subjects at risk. French Study Group on Calcitonin-Secreting Tumors (GETC). Horm Res 47 (4-6): 221-6, 1997. [PUBMED Abstract]
  7. Ponder BA: Multiple endocrine neoplasia type 2. In: Vogelstein B, Kinzler KW, eds.: The Genetic Basis of Human Cancer. 2nd ed. New York, NY: McGraw-Hill, 2002, pp 501-513.
  8. Schuffenecker I, Virally-Monod M, Brohet R, et al.: Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D'etude des Tumeurs à Calcitonine. J Clin Endocrinol Metab 83 (2): 487-91, 1998. [PUBMED Abstract]
  9. Gagel RF, Tashjian AH Jr, Cummings T, et al.: The clinical outcome of prospective screening for multiple endocrine neoplasia type 2a. An 18-year experience. N Engl J Med 318 (8): 478-84, 1988. [PUBMED Abstract]
  10. Guyétant S, Rousselet MC, Durigon M, et al.: Sex-related C cell hyperplasia in the normal human thyroid: a quantitative autopsy study. J Clin Endocrinol Metab 82 (1): 42-7, 1997. [PUBMED Abstract]
  11. LiVolsi VA: C cell hyperplasia/neoplasia. J Clin Endocrinol Metab 82 (1): 39-41, 1997. [PUBMED Abstract]
  12. Landsvater RM, Rombouts AG, te Meerman GJ, et al.: The clinical implications of a positive calcitonin test for C-cell hyperplasia in genetically unaffected members of an MEN2A kindred. Am J Hum Genet 52 (2): 335-42, 1993. [PUBMED Abstract]
  13. Lips CJ, Landsvater RM, Höppener JW, et al.: Clinical screening as compared with DNA analysis in families with multiple endocrine neoplasia type 2A. N Engl J Med 331 (13): 828-35, 1994. [PUBMED Abstract]
  14. Elisei R, Bottici V, Luchetti F, et al.: Impact of routine measurement of serum calcitonin on the diagnosis and outcome of medullary thyroid cancer: experience in 10,864 patients with nodular thyroid disorders. J Clin Endocrinol Metab 89 (1): 163-8, 2004. [PUBMED Abstract]
  15. Kudo T, Miyauchi A, Ito Y, et al.: Serum calcitonin levels with calcium loading tests before and after total thyroidectomy in patients with thyroid diseases other than medullary thyroid carcinoma. Endocr J 58 (3): 217-21, 2011. [PUBMED Abstract]
  16. Incidence: Thyroid Cancer. Bethesda, Md: National Cancer Institute, SEER, 2004. Available online. Last accessed October 16, 2013.
  17. Gharib H, McConahey WM, Tiegs RD, et al.: Medullary thyroid carcinoma: clinicopathologic features and long-term follow-up of 65 patients treated during 1946 through 1970. Mayo Clin Proc 67 (10): 934-40, 1992. [PUBMED Abstract]
  18. Decker RA, Peacock ML, Borst MJ, et al.: Progress in genetic screening of multiple endocrine neoplasia type 2A: is calcitonin testing obsolete? Surgery 118 (2): 257-63; discussion 263-4, 1995. [PUBMED Abstract]
  19. Kitamura Y, Goodfellow PJ, Shimizu K, et al.: Novel germline RET proto-oncogene mutations associated with medullary thyroid carcinoma (MTC): mutation analysis in Japanese patients with MTC. Oncogene 14 (25): 3103-6, 1997. [PUBMED Abstract]
  20. Eng C, Mulligan LM, Smith DP, et al.: Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma. Clin Endocrinol (Oxf) 43 (1): 123-7, 1995. [PUBMED Abstract]
  21. Wohllk N, Cote GJ, Bugalho MM, et al.: Relevance of RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab 81 (10): 3740-5, 1996. [PUBMED Abstract]
  22. Lips CJ: Clinical management of the multiple endocrine neoplasia syndromes: results of a computerized opinion poll at the Sixth International Workshop on Multiple Endocrine Neoplasia and von Hippel-Lindau disease. J Intern Med 243 (6): 589-94, 1998. [PUBMED Abstract]
  23. Brandi ML, Gagel RF, Angeli A, et al.: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86 (12): 5658-71, 2001. [PUBMED Abstract]
  24. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Version 2.2014. Rockledge, Pa: National Comprehensive Cancer Network, 2014. Available online with free subscription. Last accessed December 04, 2014.
  25. Kloos RT, Eng C, Evans DB, et al.: Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 19 (6): 565-612, 2009. [PUBMED Abstract]
  26. American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed November 24, 2014.
  27. Hundahl SA, Fleming ID, Fremgen AM, et al.: A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see comments] Cancer 83 (12): 2638-48, 1998. [PUBMED Abstract]
  28. Bhattacharyya N: A population-based analysis of survival factors in differentiated and medullary thyroid carcinoma. Otolaryngol Head Neck Surg 128 (1): 115-23, 2003. [PUBMED Abstract]
  29. Modigliani E, Vasen HM, Raue K, et al.: Pheochromocytoma in multiple endocrine neoplasia type 2: European study. The Euromen Study Group. J Intern Med 238 (4): 363-7, 1995. [PUBMED Abstract]
  30. Roman S, Lin R, Sosa JA: Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer 107 (9): 2134-42, 2006. [PUBMED Abstract]
  31. Bergholm U, Bergström R, Ekbom A: Long-term follow-up of patients with medullary carcinoma of the thyroid. Cancer 79 (1): 132-8, 1997. [PUBMED Abstract]
  32. Kebebew E, Ituarte PH, Siperstein AE, et al.: Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 88 (5): 1139-48, 2000. [PUBMED Abstract]
  33. Elisei R, Romei C, Cosci B, et al.: RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin Endocrinol Metab 92 (12): 4725-9, 2007. [PUBMED Abstract]
  34. Paszko Z, Sromek M, Czetwertynska M, et al.: The occurrence and the type of germline mutations in the RET gene in patients with medullary thyroid carcinoma and their unaffected kindred's from Central Poland. Cancer Invest 25 (8): 742-9, 2007. [PUBMED Abstract]
  35. Pelizzo MR, Boschin IM, Bernante P, et al.: Natural history, diagnosis, treatment and outcome of medullary thyroid cancer: 37 years experience on 157 patients. Eur J Surg Oncol 33 (4): 493-7, 2007. [PUBMED Abstract]
  36. Lenders JW, Pacak K, Walther MM, et al.: Biochemical diagnosis of pheochromocytoma: which test is best? JAMA 287 (11): 1427-34, 2002. [PUBMED Abstract]
  37. Gerlo EA, Sevens C: Urinary and plasma catecholamines and urinary catecholamine metabolites in pheochromocytoma: diagnostic value in 19 cases. Clin Chem 40 (2): 250-6, 1994. [PUBMED Abstract]
  38. Guller U, Turek J, Eubanks S, et al.: Detecting pheochromocytoma: defining the most sensitive test. Ann Surg 243 (1): 102-7, 2006. [PUBMED Abstract]
  39. Raber W, Raffesberg W, Bischof M, et al.: Diagnostic efficacy of unconjugated plasma metanephrines for the detection of pheochromocytoma. Arch Intern Med 160 (19): 2957-63, 2000. [PUBMED Abstract]
  40. Sawka AM, Jaeschke R, Singh RJ, et al.: A comparison of biochemical tests for pheochromocytoma: measurement of fractionated plasma metanephrines compared with the combination of 24-hour urinary metanephrines and catecholamines. J Clin Endocrinol Metab 88 (2): 553-8, 2003. [PUBMED Abstract]
  41. Unger N, Pitt C, Schmidt IL, et al.: Diagnostic value of various biochemical parameters for the diagnosis of pheochromocytoma in patients with adrenal mass. Eur J Endocrinol 154 (3): 409-17, 2006. [PUBMED Abstract]
  42. Pacak K, Eisenhofer G, Ahlman H, et al.: Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005. Nat Clin Pract Endocrinol Metab 3 (2): 92-102, 2007. [PUBMED Abstract]
  43. van der Harst E, de Herder WW, Bruining HA, et al.: [(123)I]metaiodobenzylguanidine and [(111)In]octreotide uptake in begnign and malignant pheochromocytomas. J Clin Endocrinol Metab 86 (2): 685-93, 2001. [PUBMED Abstract]
  44. Pacak K, Linehan WM, Eisenhofer G, et al.: Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma. Ann Intern Med 134 (4): 315-29, 2001. [PUBMED Abstract]
  45. Kaelin WG Jr: Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2 (9): 673-82, 2002. [PUBMED Abstract]
  46. Maher ER, Eng C: The pressure rises: update on the genetics of phaeochromocytoma. Hum Mol Genet 11 (20): 2347-54, 2002. [PUBMED Abstract]
  47. Neumann HP, Bausch B, McWhinney SR, et al.: Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 346 (19): 1459-66, 2002. [PUBMED Abstract]
  48. Amar L, Bertherat J, Baudin E, et al.: Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 23 (34): 8812-8, 2005. [PUBMED Abstract]
  49. Gimenez-Roqueplo AP, Lehnert H, Mannelli M, et al.: Phaeochromocytoma, new genes and screening strategies. Clin Endocrinol (Oxf) 65 (6): 699-705, 2006. [PUBMED Abstract]
  50. Jafri M, Whitworth J, Rattenberry E, et al.: Evaluation of SDHB, SDHD and VHL gene susceptibility testing in the assessment of individuals with non-syndromic phaeochromocytoma, paraganglioma and head and neck paraganglioma. Clin Endocrinol (Oxf) 78 (6): 898-906, 2013. [PUBMED Abstract]
  51. Comino-Méndez I, Gracia-Aznárez FJ, Schiavi F, et al.: Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 43 (7): 663-7, 2011. [PUBMED Abstract]
  52. Neumann HP, Sullivan M, Winter A, et al.: Germline mutations of the TMEM127 gene in patients with paraganglioma of head and neck and extraadrenal abdominal sites. J Clin Endocrinol Metab 96 (8): E1279-82, 2011. [PUBMED Abstract]
  53. Burnichon N, Lepoutre-Lussey C, Laffaire J, et al.: A novel TMEM127 mutation in a patient with familial bilateral pheochromocytoma. Eur J Endocrinol 164 (1): 141-5, 2011. [PUBMED Abstract]
  54. Bayley JP, Kunst HP, Cascon A, et al.: SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. Lancet Oncol 11 (4): 366-72, 2010. [PUBMED Abstract]
  55. Neumann HP, Erlic Z, Boedeker CC, et al.: Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out. Cancer Res 69 (8): 3650-6, 2009. [PUBMED Abstract]
  56. Erlic Z, Rybicki L, Peczkowska M, et al.: Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients. Clin Cancer Res 15 (20): 6378-85, 2009. [PUBMED Abstract]
  57. Mannelli M, Castellano M, Schiavi F, et al.: Clinically guided genetic screening in a large cohort of italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab 94 (5): 1541-7, 2009. [PUBMED Abstract]
  58. Fraser WD: Hyperparathyroidism. Lancet 374 (9684): 145-58, 2009. [PUBMED Abstract]
  59. Tonelli F, Marcucci T, Giudici F, et al.: Surgical approach in hereditary hyperparathyroidism. Endocr J 56 (7): 827-41, 2009. [PUBMED Abstract]
  60. Villablanca A, Calender A, Forsberg L, et al.: Germline and de novo mutations in the HRPT2 tumour suppressor gene in familial isolated hyperparathyroidism (FIHP). J Med Genet 41 (3): e32, 2004. [PUBMED Abstract]
  61. Marx SJ, Simonds WF, Agarwal SK, et al.: Hyperparathyroidism in hereditary syndromes: special expressions and special managements. J Bone Miner Res 17 (Suppl 2): N37-43, 2002. [PUBMED Abstract]
  62. Sipple JH: The association of pheochromocytoma with carcinoma of the thyroid gland. Am J Med 31 (1): 163-166, 1961.
  63. Eng C, Clayton D, Schuffenecker I, et al.: The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 276 (19): 1575-9, 1996. [PUBMED Abstract]
  64. Sanso GE, Domene HM, Garcia R, et al.: Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: presence of C-cell malignant disease in asymptomatic carriers. Cancer 94 (2): 323-30, 2002. [PUBMED Abstract]
  65. Yip L, Cote GJ, Shapiro SE, et al.: Multiple endocrine neoplasia type 2: evaluation of the genotype-phenotype relationship. Arch Surg 138 (4): 409-16; discussion 416, 2003. [PUBMED Abstract]
  66. Raue F, Frank-Raue K, Grauer A: Multiple endocrine neoplasia type 2. Clinical features and screening. Endocrinol Metab Clin North Am 23 (1): 137-56, 1994. [PUBMED Abstract]
  67. Perren A, Komminoth P: Familial pheochromocytomas and paragangliomas: stories from the sign-out room. Endocr Pathol 17 (4): 337-44, 2006. [PUBMED Abstract]
  68. Webb TA, Sheps SG, Carney JA: Differences between sporadic pheochromocytoma and pheochromocytoma in multiple endocrime neoplasia, type 2. Am J Surg Pathol 4 (2): 121-6, 1980. [PUBMED Abstract]
  69. Lips KJ, Van der Sluys Veer J, Struyvenberg A, et al.: Bilateral occurrence of pheochromocytoma in patients with the multiple endocrine neoplasia syndrome type 2A (Sipple's syndrome). Am J Med 70 (5): 1051-60, 1981. [PUBMED Abstract]
  70. Neumann HP, Berger DP, Sigmund G, et al.: Pheochromocytomas, multiple endocrine neoplasia type 2, and von Hippel-Lindau disease. N Engl J Med 329 (21): 1531-8, 1993. [PUBMED Abstract]
  71. Kraimps JL, Denizot A, Carnaille B, et al.: Primary hyperparathyroidism in multiple endocrine neoplasia type IIa: retrospective French multicentric study. Groupe d'Etude des Tumeurs á Calcitonine (GETC, French Calcitonin Tumors Study Group), French Association of Endocrine Surgeons. World J Surg 20 (7): 808-12; discussion 812-3, 1996. [PUBMED Abstract]
  72. Benson L, Ljunghall S, Akerström G, et al.: Hyperparathyroidism presenting as the first lesion in multiple endocrine neoplasia type 1. Am J Med 82 (4): 731-7, 1987. [PUBMED Abstract]
  73. Trump D, Farren B, Wooding C, et al.: Clinical studies of multiple endocrine neoplasia type 1 (MEN1) QJM 89 (9): 653-69, 1996. [PUBMED Abstract]
  74. Vasen HF, Lamers CB, Lips CJ: Screening for the multiple endocrine neoplasia syndrome type I. A study of 11 kindreds in The Netherlands. Arch Intern Med 149 (12): 2717-22, 1989. [PUBMED Abstract]
  75. Bugalho MJ, Limbert E, Sobrinho LG, et al.: A kindred with multiple endocrine neoplasia type 2A associated with pruritic skin lesions. Cancer 70 (11): 2664-7, 1992. [PUBMED Abstract]
  76. Robinson MF, Furst EJ, Nunziata V, et al.: Characterization of the clinical features of five families with hereditary primary cutaneous lichen amyloidosis and multiple endocrine neoplasia type 2. Henry Ford Hosp Med J 40 (3-4): 249-52, 1992. [PUBMED Abstract]
  77. Kouvaraki MA, Shapiro SE, Perrier ND, et al.: RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid 15 (6): 531-44, 2005. [PUBMED Abstract]
  78. Pacini F, Castagna MG, Cipri C, et al.: Medullary thyroid carcinoma. Clin Oncol (R Coll Radiol) 22 (6): 475-85, 2010. [PUBMED Abstract]
  79. Morrison PJ, Nevin NC: Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann-Froboese syndrome). J Med Genet 33 (9): 779-82, 1996. [PUBMED Abstract]
  80. Gorlin RJ, Sedano HO, Vickers RA, et al.: Multiple mucosal neuromas, pheochromocytoma and medullary carcinoma of the thyroid--a syndrome. Cancer 22 (2): 293-9 passim, 1968. [PUBMED Abstract]
  81. Gorlin RJ, Vickers RA: Multiple mucosal neuromas, pheochromocytoma, medullary carcinoma of the thyroid and marfanoid body build with muscle wasting: reexamination of a syndrome of neural crest malmigration. Birth Defects Orig Artic Ser 7 (6): 69-72, 1971. [PUBMED Abstract]
  82. Skinner MA, DeBenedetti MK, Moley JF, et al.: Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. J Pediatr Surg 31 (1): 177-81; discussion 181-2, 1996. [PUBMED Abstract]
  83. O'Riordain DS, O'Brien T, Weaver AL, et al.: Medullary thyroid carcinoma in multiple endocrine neoplasia types 2A and 2B. Surgery 116 (6): 1017-23, 1994. [PUBMED Abstract]
  84. Vasen HF, van der Feltz M, Raue F, et al.: The natural course of multiple endocrine neoplasia type IIb. A study of 18 cases. Arch Intern Med 152 (6): 1250-2, 1992. [PUBMED Abstract]
  85. Romeo G, Ceccherini I, Celli J, et al.: Association of multiple endocrine neoplasia type 2 and Hirschsprung disease. J Intern Med 243 (6): 515-20, 1998. [PUBMED Abstract]
  86. Decker RA, Peacock ML, Watson P: Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. Hum Mol Genet 7 (1): 129-34, 1998. [PUBMED Abstract]
  87. Carrasquillo MM, McCallion AS, Puffenberger EG, et al.: Genome-wide association study and mouse model identify interaction between RET and EDNRB pathways in Hirschsprung disease. Nat Genet 32 (2): 237-44, 2002. [PUBMED Abstract]
  88. Mulligan LM, Eng C, Attié T, et al.: Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. Hum Mol Genet 3 (12): 2163-7, 1994. [PUBMED Abstract]
  89. Emison ES, McCallion AS, Kashuk CS, et al.: A common sex-dependent mutation in a RET enhancer underlies Hirschsprung disease risk. Nature 434 (7035): 857-63, 2005. [PUBMED Abstract]
  90. Gardner E, Papi L, Easton DF, et al.: Genetic linkage studies map the multiple endocrine neoplasia type 2 loci to a small interval on chromosome 10q11.2. Hum Mol Genet 2 (3): 241-6, 1993. [PUBMED Abstract]
  91. Mole SE, Mulligan LM, Healey CS, et al.: Localisation of the gene for multiple endocrine neoplasia type 2A to a 480 kb region in chromosome band 10q11.2. Hum Mol Genet 2 (3): 247-52, 1993. [PUBMED Abstract]
  92. Takahashi M, Ritz J, Cooper GM: Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 42 (2): 581-8, 1985. [PUBMED Abstract]
  93. Kwok JB, Gardner E, Warner JP, et al.: Structural analysis of the human ret proto-oncogene using exon trapping. Oncogene 8 (9): 2575-82, 1993. [PUBMED Abstract]
  94. Myers SM, Eng C, Ponder BA, et al.: Characterization of RET proto-oncogene 3' splicing variants and polyadenylation sites: a novel C-terminus for RET. Oncogene 11 (10): 2039-45, 1995. [PUBMED Abstract]
  95. Airaksinen MS, Saarma M: The GDNF family: signalling, biological functions and therapeutic value. Nat Rev Neurosci 3 (5): 383-94, 2002. [PUBMED Abstract]
  96. Takaya K, Yoshimasa T, Arai H, et al.: Expression of the RET proto-oncogene in normal human tissues, pheochromocytomas, and other tumors of neural crest origin. J Mol Med 74 (10): 617-21, 1996. [PUBMED Abstract]
  97. Kurokawa K, Kawai K, Hashimoto M, et al.: Cell signalling and gene expression mediated by RET tyrosine kinase. J Intern Med 253 (6): 627-33, 2003. [PUBMED Abstract]
  98. Manié S, Santoro M, Fusco A, et al.: The RET receptor: function in development and dysfunction in congenital malformation. Trends Genet 17 (10): 580-9, 2001. [PUBMED Abstract]
  99. Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010. [PUBMED Abstract]
  100. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. Am J Hum Genet 57 (5): 1233-41, 1995. [PUBMED Abstract]
  101. Cooper DS, Doherty GM, Haugen BR, et al.: Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 19 (11): 1167-214, 2009. [PUBMED Abstract]
  102. Ceccherini I, Hofstra RM, Luo Y, et al.: DNA polymorphisms and conditions for SSCP analysis of the 20 exons of the ret proto-oncogene. Oncogene 9 (10): 3025-9, 1994. [PUBMED Abstract]
  103. Xue F, Yu H, Maurer LH, et al.: Germline RET mutations in MEN 2A and FMTC and their detection by simple DNA diagnostic tests. Hum Mol Genet 3 (4): 635-8, 1994. [PUBMED Abstract]
  104. McMahon R, Mulligan LM, Healey CS, et al.: Direct, non-radioactive detection of mutations in multiple endocrine neoplasia type 2A families. Hum Mol Genet 3 (4): 643-6, 1994. [PUBMED Abstract]
  105. Kambouris M, Jackson CE, Feldman GL: Diagnosis of multiple endocrine neoplasia [MEN] 2A, 2B and familial medullary thyroid cancer [FMTC] by multiplex PCR and heteroduplex analyses of RET proto-oncogene mutations. Hum Mutat 8 (1): 64-70, 1996. [PUBMED Abstract]
  106. Machens A, Niccoli-Sire P, Hoegel J, et al.: Early malignant progression of hereditary medullary thyroid cancer. N Engl J Med 349 (16): 1517-25, 2003. [PUBMED Abstract]
  107. Elisei R, Romei C, Renzini G, et al.: The timing of total thyroidectomy in RET gene mutation carriers could be personalized and safely planned on the basis of serum calcitonin: 18 years experience at one single center. J Clin Endocrinol Metab 97 (2): 426-35, 2012. [PUBMED Abstract]
  108. Eng C, Smith DP, Mulligan LM, et al.: Point mutation within the tyrosine kinase domain of the RET proto-oncogene in multiple endocrine neoplasia type 2B and related sporadic tumours. Hum Mol Genet 3 (2): 237-41, 1994. [PUBMED Abstract]
  109. Hofstra RM, Landsvater RM, Ceccherini I, et al.: A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 367 (6461): 375-6, 1994. [PUBMED Abstract]
  110. Carlson KM, Dou S, Chi D, et al.: Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci U S A 91 (4): 1579-83, 1994. [PUBMED Abstract]
  111. Gimm O, Marsh DJ, Andrew SD, et al.: Germline dinucleotide mutation in codon 883 of the RET proto-oncogene in multiple endocrine neoplasia type 2B without codon 918 mutation. J Clin Endocrinol Metab 82 (11): 3902-4, 1997. [PUBMED Abstract]
  112. Smith DP, Houghton C, Ponder BA: Germline mutation of RET codon 883 in two cases of de novo MEN 2B. Oncogene 15 (10): 1213-7, 1997. [PUBMED Abstract]
  113. Eng C, Mulligan LM, Healey CS, et al.: Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma. Cancer Res 56 (9): 2167-70, 1996. [PUBMED Abstract]
  114. Cranston AN, Carniti C, Oakhill K, et al.: RET is constitutively activated by novel tandem mutations that alter the active site resulting in multiple endocrine neoplasia type 2B. Cancer Res 66 (20): 10179-87, 2006. [PUBMED Abstract]
  115. Miyauchi A, Futami H, Hai N, et al.: Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation. Jpn J Cancer Res 90 (1): 1-5, 1999. [PUBMED Abstract]
  116. Kameyama K, Okinaga H, Takami H: RET oncogene mutations in 75 cases of familial medullary thyroid carcinoma in Japan. Biomed Pharmacother 58 (6-7): 345-7, 2004 Jul-Aug. [PUBMED Abstract]
  117. Iwashita T, Murakami H, Kurokawa K, et al.: A two-hit model for development of multiple endocrine neoplasia type 2B by RET mutations. Biochem Biophys Res Commun 268 (3): 804-8, 2000. [PUBMED Abstract]
  118. Menko FH, van der Luijt RB, de Valk IA, et al.: Atypical MEN type 2B associated with two germline RET mutations on the same allele not involving codon 918. J Clin Endocrinol Metab 87 (1): 393-7, 2002. [PUBMED Abstract]
  119. Mulligan LM, Eng C, Healey CS, et al.: Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet 6 (1): 70-4, 1994. [PUBMED Abstract]
  120. Seri M, Celli I, Betsos N, et al.: A Cys634Gly substitution of the RET proto-oncogene in a family with recurrence of multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis. Clin Genet 51 (2): 86-90, 1997. [PUBMED Abstract]
  121. Rothberg AE, Raymond VM, Gruber SB, et al.: Familial medullary thyroid carcinoma associated with cutaneous lichen amyloidosis. Thyroid 19 (6): 651-5, 2009. [PUBMED Abstract]
  122. Quayle FJ, Fialkowski EA, Benveniste R, et al.: Pheochromocytoma penetrance varies by RET mutation in MEN 2A. Surgery 142 (6): 800-5; discussion 805.e1, 2007. [PUBMED Abstract]
  123. Bolino A, Schuffenecker I, Luo Y, et al.: RET mutations in exons 13 and 14 of FMTC patients. Oncogene 10 (12): 2415-9, 1995. [PUBMED Abstract]
  124. Boccia LM, Green JS, Joyce C, et al.: Mutation of RET codon 768 is associated with the FMTC phenotype. Clin Genet 51 (2): 81-5, 1997. [PUBMED Abstract]
  125. Lesueur F, Cebrian A, Cranston A, et al.: Germline homozygous mutations at codon 804 in the RET protooncogene in medullary thyroid carcinoma/multiple endocrine neoplasia type 2A patients. J Clin Endocrinol Metab 90 (6): 3454-7, 2005. [PUBMED Abstract]
  126. Shannon KE, Gimm O, Hinze R: Germline V804M mutation in the RET protooncogene in 2 apparently sporadic cases of MTC presenting in the 7th decade of life. The Journal of Endocrine Genetics 1 (1): 39-46, 1999.
  127. Raue F, Frank-Raue K: Genotype-phenotype relationship in multiple endocrine neoplasia type 2. Implications for clinical management. Hormones (Athens) 8 (1): 23-8, 2009 Jan-Mar. [PUBMED Abstract]
  128. Frank-Raue K, Rybicki LA, Erlic Z, et al.: Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat 32 (1): 51-8, 2011. [PUBMED Abstract]
  129. Mulligan LM, Marsh DJ, Robinson BG, et al.: Genotype-phenotype correlation in multiple endocrine neoplasia type 2: report of the International RET Mutation Consortium. J Intern Med 238 (4): 343-6, 1995. [PUBMED Abstract]
  130. Moers AM, Landsvater RM, Schaap C, et al.: Familial medullary thyroid carcinoma: not a distinct entity? Genotype-phenotype correlation in a large family. Am J Med 101 (6): 635-41, 1996. [PUBMED Abstract]
  131. Niccoli-Sire P, Murat A, Rohmer V, et al.: Familial medullary thyroid carcinoma with noncysteine ret mutations: phenotype-genotype relationship in a large series of patients. J Clin Endocrinol Metab 86 (8): 3746-53, 2001. [PUBMED Abstract]
  132. Machens A, Ukkat J, Brauckhoff M, et al.: Advances in the management of hereditary medullary thyroid cancer. J Intern Med 257 (1): 50-9, 2005. [PUBMED Abstract]
  133. Mukherjee S, Zakalik D: RET codon 804 mutations in multiple endocrine neoplasia 2: genotype-phenotype correlations and implications in clinical management. Clin Genet 79 (1): 1-16, 2011. [PUBMED Abstract]
  134. Dvorakova S, Vaclavikova E, Duskova J, et al.: Exon 5 of the RET proto-oncogene: a newly detected risk exon for familial medullary thyroid carcinoma, a novel germ-line mutation Gly321Arg. J Endocrinol Invest 28 (10): 905-9, 2005. [PUBMED Abstract]
  135. Muzza M, Cordella D, Bombled J, et al.: Four novel RET germline variants in exons 8 and 11 display an oncogenic potential in vitro. Eur J Endocrinol 162 (4): 771-7, 2010. [PUBMED Abstract]
  136. Pigny P, Bauters C, Wemeau JL, et al.: A novel 9-base pair duplication in RET exon 8 in familial medullary thyroid carcinoma. J Clin Endocrinol Metab 84 (5): 1700-4, 1999. [PUBMED Abstract]
  137. Niccoli-Sire P, Murat A, Rohmer V, et al.: When should thyroidectomy be performed in familial medullary thyroid carcinoma gene carriers with non-cysteine RET mutations? Surgery 134 (6): 1029-36; discussion 1036-7, 2003. [PUBMED Abstract]
  138. Fazioli F, Piccinini G, Appolloni G, et al.: A new germline point mutation in Ret exon 8 (cys515ser) in a family with medullary thyroid carcinoma. Thyroid 18 (7): 775-82, 2008. [PUBMED Abstract]
  139. Da Silva AM, Maciel RM, Da Silva MR, et al.: A novel germ-line point mutation in RET exon 8 (Gly(533)Cys) in a large kindred with familial medullary thyroid carcinoma. J Clin Endocrinol Metab 88 (11): 5438-43, 2003. [PUBMED Abstract]
  140. Bethanis S, Koutsodontis G, Palouka T, et al.: A newly detected mutation of the RET protooncogene in exon 8 as a cause of multiple endocrine neoplasia type 2A. Hormones (Athens) 6 (2): 152-6, 2007 Apr-Jun. [PUBMED Abstract]
  141. Kaldrymides P, Mytakidis N, Anagnostopoulos T, et al.: A rare RET gene exon 8 mutation is found in two Greek kindreds with familial medullary thyroid carcinoma: implications for screening. Clin Endocrinol (Oxf) 64 (5): 561-6, 2006. [PUBMED Abstract]
  142. Peppa M, Boutati E, Kamakari S, et al.: Multiple endocrine neoplasia type 2A in two families with the familial medullary thyroid carcinoma associated G533C mutation of the RET proto-oncogene. Eur J Endocrinol 159 (6): 767-71, 2008. [PUBMED Abstract]
  143. Oliveira MN, Hemerly JP, Bastos AU, et al.: The RET p.G533C mutation confers predisposition to multiple endocrine neoplasia type 2A in a Brazilian kindred and is able to induce a malignant phenotype in vitro and in vivo. Thyroid 21 (9): 975-85, 2011. [PUBMED Abstract]
  144. Sáez ME, Ruiz A, Cebrián A, et al.: A new germline mutation, R600Q, within the coding region of RET proto-oncogene: a rare polymorphism or a MEN 2 causing mutation? Hum Mutat 15 (1): 122, 2000. [PUBMED Abstract]
  145. Rey JM, Brouillet JP, Fonteneau-Allaire J, et al.: Novel germline RET mutation segregating with papillary thyroid carcinomas. Genes Chromosomes Cancer 32 (4): 390-1, 2001. [PUBMED Abstract]
  146. Ahmed SA, Snow-Bailey K, Highsmith WE, et al.: Nine novel germline gene variants in the RET proto-oncogene identified in twelve unrelated cases. J Mol Diagn 7 (2): 283-8, 2005. [PUBMED Abstract]
  147. Ercolino T, Lombardi A, Becherini L, et al.: The Y606C RET mutation causes a receptor gain of function. Clin Endocrinol (Oxf) 69 (2): 253-8, 2008. [PUBMED Abstract]
  148. Igaz P, Patócs A, Rácz K, et al.: Occurrence of pheochromocytoma in a MEN2A family with codon 609 mutation of the RET proto-oncogene. J Clin Endocrinol Metab 87 (6): 2994, 2002. [PUBMED Abstract]
  149. Fialkowski EA, DeBenedetti MK, Moley JF, et al.: RET proto-oncogene testing in infants presenting with Hirschsprung disease identifies 2 new multiple endocrine neoplasia 2A kindreds. J Pediatr Surg 43 (1): 188-90, 2008. [PUBMED Abstract]
  150. Mian C, Barollo S, Zambonin L, et al.: Characterization of the largest kindred with MEN2A due to a Cys609Ser RET mutation. Fam Cancer 8 (4): 379-82, 2009. [PUBMED Abstract]
  151. Kinlaw WB, Scott SM, Maue RA, et al.: Multiple endocrine neoplasia 2A due to a unique C609S RET mutation presents with pheochromocytoma and reduced penetrance of medullary thyroid carcinoma. Clin Endocrinol (Oxf) 63 (6): 676-82, 2005. [PUBMED Abstract]
  152. Calva D, O'Dorisio TM, Sue O'Dorisio M, et al.: When is prophylactic thyroidectomy indicated for patients with the RET codon 609 mutation? Ann Surg Oncol 16 (8): 2237-44, 2009. [PUBMED Abstract]
  153. Jung J, Uchino S, Lee Y, et al.: A Korean family of familial medullary thyroid cancer with Cys618Ser RET germline mutation. J Korean Med Sci 25 (2): 226-9, 2010. [PUBMED Abstract]
  154. Qi XP, Ying RB, Ma JM, et al.: Case report: a p.C618S RET proto-oncogene germline mutation in a large Chinese pedigree with familial medullary thyroid carcinoma. Fam Cancer 11 (1): 131-6, 2012. [PUBMED Abstract]
  155. Hedayati M, Zarif Yeganeh M, Sheikhol Eslami S, et al.: Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma. J Thyroid Res 2011: 264248, 2011. [PUBMED Abstract]
  156. Neocleous V, Skordis N, Portides G, et al.: RET proto-oncogene mutations are restricted to codon 618 in Cypriot families with multiple endocrine neoplasia 2. J Endocrinol Invest 34 (10): 764-9, 2011. [PUBMED Abstract]
  157. Chu CS, Lee KT, Lee ST, et al.: Effects of atorvastatin on ventricular late potentials and repolarization dispersion in patients with hypercholesterolemia. Kaohsiung J Med Sci 23 (5): 217-24, 2007. [PUBMED Abstract]
  158. Berndt I, Reuter M, Saller B, et al.: A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab 83 (3): 770-4, 1998. [PUBMED Abstract]
  159. Elston MS, Meyer-Rochow GY, Holdaway I, et al.: Patients with RET D631Y mutations most commonly present with pheochromocytoma and not medullary thyroid carcinoma. Horm Metab Res 44 (5): 339-42, 2012. [PUBMED Abstract]
  160. Asai N, Iwashita T, Murakami H, et al.: Mechanism of Ret activation by a mutation at aspartic acid 631 identified in sporadic pheochromocytoma. Biochem Biophys Res Commun 255 (3): 587-90, 1999. [PUBMED Abstract]
  161. Höppner W, Dralle H, Brabant G: Duplication of 9 base pairs in the critical cysteine-rich domain of the RET proto-oncogene causes multiple endocrine neoplasia type 2A. Hum Mutat Suppl (1): S128-30, 1998. [PUBMED Abstract]
  162. Puñales MK, Graf H, Gross JL, et al.: RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab 88 (6): 2644-9, 2003. [PUBMED Abstract]
  163. Zhou YL, Zhu SX, Li JJ, et al.: [The clinical patterns and RET proto-oncogene in fifteen multiple endocrine neoplasia type 2A pedigrees]. Zhonghua Nei Ke Za Zhi 46 (6): 466-70, 2007. [PUBMED Abstract]
  164. Lemos MC, Carrilho F, Rodrigues FJ, et al.: Early onset of medullary thyroid carcinoma in a kindred with multiple endocrine neoplasia type iia associated with cutaneous lichen amyloidosis. Endocr Pract 8 (1): 19-22, 2002 Jan-Feb. [PUBMED Abstract]
  165. Toledo RA, Wagner SM, Coutinho FL, et al.: High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene. J Clin Endocrinol Metab 95 (3): 1318-27, 2010. [PUBMED Abstract]
  166. Höppner W, Ritter MM: A duplication of 12 bp in the critical cysteine rich domain of the RET proto-oncogene results in a distinct phenotype of multiple endocrine neoplasia type 2A. Hum Mol Genet 6 (4): 587-90, 1997. [PUBMED Abstract]
  167. Wiench M, Wygoda Z, Gubala E, et al.: Estimation of risk of inherited medullary thyroid carcinoma in apparent sporadic patients. J Clin Oncol 19 (5): 1374-80, 2001. [PUBMED Abstract]
  168. Colombo-Benkmann M, Li Z, Riemann B, et al.: Characterization of the RET protooncogene transmembrane domain mutation S649L associated with nonaggressive medullary thyroid carcinoma. Eur J Endocrinol 158 (6): 811-6, 2008. [PUBMED Abstract]
  169. Vierhapper H, Bieglmayer C, Heinze G, et al.: Frequency of RET proto-oncogene mutations in patients with normal and with moderately elevated pentagastrin-stimulated serum concentrations of calcitonin. Thyroid 14 (8): 580-3, 2004. [PUBMED Abstract]
  170. Borrello MG, Aiello A, Peissel B, et al.: Functional characterization of the MTC-associated germline RET-K666E mutation: evidence of oncogenic potential enhanced by the G691S polymorphism. Endocr Relat Cancer 18 (4): 519-27, 2011. [PUBMED Abstract]
  171. Dabir T, Hunter SJ, Russell CF, et al.: The RET mutation E768D confers a late-onset familial medullary thyroid carcinoma -- only phenotype with incomplete penetrance: implications for screening and management of carrier status. Fam Cancer 5 (2): 201-4, 2006. [PUBMED Abstract]
  172. Frank-Raue K, Döhring J, Scheumann G, et al.: New mutations in the RET protooncogene-L881V - associated with medullary thyroid carcinoma and -R770Q - in a patient with mixed medullar/follicular thyroid tumour. Exp Clin Endocrinol Diabetes 118 (8): 550-3, 2010. [PUBMED Abstract]
  173. D'Aloiso L, Carlomagno F, Bisceglia M, et al.: Clinical case seminar: in vivo and in vitro characterization of a novel germline RET mutation associated with low-penetrant nonaggressive familial medullary thyroid carcinoma. J Clin Endocrinol Metab 91 (3): 754-9, 2006. [PUBMED Abstract]
  174. Frank-Raue K, Machens A, Scheuba C, et al.: Difference in development of medullary thyroid carcinoma among carriers of RET mutations in codons 790 and 791. Clin Endocrinol (Oxf) 69 (2): 259-63, 2008. [PUBMED Abstract]
  175. Bihan H, Baudin E, Meas T, et al.: Role of prophylactic thyroidectomy in RET 790 familial medullary thyroid carcinoma. Head Neck 34 (4): 493-8, 2012. [PUBMED Abstract]
  176. Vestergaard P, Vestergaard EM, Brockstedt H, et al.: Codon Y791F mutations in a large kindred: is prophylactic thyroidectomy always indicated? World J Surg 31 (5): 996-1001; discussion 1002-4, 2007. [PUBMED Abstract]
  177. Learoyd DL, Gosnell J, Elston MS, et al.: Experience of prophylactic thyroidectomy in multiple endocrine neoplasia type 2A kindreds with RET codon 804 mutations. Clin Endocrinol (Oxf) 63 (6): 636-41, 2005. [PUBMED Abstract]
  178. Lal G, Nowell AG, Liao J, et al.: Determinants of survival in patients with calciphylaxis: a multivariate analysis. Surgery 146 (6): 1028-34, 2009. [PUBMED Abstract]
  179. Shifrin AL, Ogilvie JB, Stang MT, et al.: Single nucleotide polymorphisms act as modifiers and correlate with the development of medullary and simultaneous medullary/papillary thyroid carcinomas in 2 large, non-related families with the RET V804M proto-oncogene mutation. Surgery 148 (6): 1274-80; discussion 1280-1, 2010. [PUBMED Abstract]
  180. Kasprzak L, Nolet S, Gaboury L, et al.: Familial medullary thyroid carcinoma and prominent corneal nerves associated with the germline V804M and V778I mutations on the same allele of RET. J Med Genet 38 (11): 784-7, 2001. [PUBMED Abstract]
  181. Cranston A, Carniti C, Martin S, et al.: A novel activating mutation in the RET tyrosine kinase domain mediates neoplastic transformation. Mol Endocrinol 20 (7): 1633-43, 2006. [PUBMED Abstract]
  182. Jasim S, Ying AK, Waguespack SG, et al.: Multiple endocrine neoplasia type 2B with a RET proto-oncogene A883F mutation displays a more indolent form of medullary thyroid carcinoma compared with a RET M918T mutation. Thyroid 21 (2): 189-92, 2011. [PUBMED Abstract]
  183. Prazeres HJ, Rodrigues F, Figueiredo P, et al.: Occurrence of the Cys611Tyr mutation and a novel Arg886Trp substitution in the RET proto-oncogene in multiple endocrine neoplasia type 2 families and sporadic medullary thyroid carcinoma cases originating from the central region of Portugal. Clin Endocrinol (Oxf) 64 (6): 659-66, 2006. [PUBMED Abstract]
  184. Schulte KM, Machens A, Fugazzola L, et al.: The clinical spectrum of multiple endocrine neoplasia type 2a caused by the rare intracellular RET mutation S891A. J Clin Endocrinol Metab 95 (9): E92-7, 2010. [PUBMED Abstract]
  185. Hofstra RM, Fattoruso O, Quadro L, et al.: A novel point mutation in the intracellular domain of the ret protooncogene in a family with medullary thyroid carcinoma. J Clin Endocrinol Metab 82 (12): 4176-8, 1997. [PUBMED Abstract]
  186. Dang GT, Cote GJ, Schultz PN, et al.: A codon 891 exon 15 RET proto-oncogene mutation in familial medullary thyroid carcinoma: a detection strategy. Mol Cell Probes 13 (1): 77-9, 1999. [PUBMED Abstract]
  187. Jimenez C, Habra MA, Huang SC, et al.: Pheochromocytoma and medullary thyroid carcinoma: a new genotype-phenotype correlation of the RET protooncogene 891 germline mutation. J Clin Endocrinol Metab 89 (8): 4142-5, 2004. [PUBMED Abstract]
  188. Jimenez C, Dang GT, Schultz PN, et al.: A novel point mutation of the RET protooncogene involving the second intracellular tyrosine kinase domain in a family with medullary thyroid carcinoma. J Clin Endocrinol Metab 89 (7): 3521-6, 2004. [PUBMED Abstract]
  189. Zenaty D, Aigrain Y, Peuchmaur M, et al.: Medullary thyroid carcinoma identified within the first year of life in children with hereditary multiple endocrine neoplasia type 2A (codon 634) and 2B. Eur J Endocrinol 160 (5): 807-13, 2009. [PUBMED Abstract]
  190. Margraf RL, Crockett DK, Krautscheid PM, et al.: Multiple endocrine neoplasia type 2 RET protooncogene database: repository of MEN2-associated RET sequence variation and reference for genotype/phenotype correlations. Hum Mutat 30 (4): 548-56, 2009. [PUBMED Abstract]
  191. Qi XP, Zhao JQ, Du ZF, et al.: Prophylactic thyroidectomy for MEN 2-related medullary thyroid carcinoma based on predictive testing for RET proto-oncogene mutation and basal serum calcitonin in China. Eur J Surg Oncol 39 (9): 1007-12, 2013. [PUBMED Abstract]
  192. Schreinemakers JM, Vriens MR, Valk GD, et al.: Factors predicting outcome of total thyroidectomy in young patients with multiple endocrine neoplasia type 2: a nationwide long-term follow-up study. World J Surg 34 (4): 852-60, 2010. [PUBMED Abstract]
  193. Niccoli-Sire P, Murat A, Baudin E, et al.: Early or prophylactic thyroidectomy in MEN 2/FMTC gene carriers: results in 71 thyroidectomized patients. The French Calcitonin Tumours Study Group (GETC). Eur J Endocrinol 141 (5): 468-74, 1999. [PUBMED Abstract]
  194. Wells SA Jr, Skinner MA: Prophylactic thyroidectomy, based on direct genetic testing, in patients at risk for the multiple endocrine neoplasia type 2 syndromes. Exp Clin Endocrinol Diabetes 106 (1): 29-34, 1998. [PUBMED Abstract]
  195. Szinnai G, Meier C, Komminoth P, et al.: Review of multiple endocrine neoplasia type 2A in children: therapeutic results of early thyroidectomy and prognostic value of codon analysis. Pediatrics 111 (2): E132-9, 2003. [PUBMED Abstract]
  196. Skinner MA, Moley JA, Dilley WG, et al.: Prophylactic thyroidectomy in multiple endocrine neoplasia type 2A. N Engl J Med 353 (11): 1105-13, 2005. [PUBMED Abstract]
  197. Machens A, Schneyer U, Holzhausen HJ, et al.: Prospects of remission in medullary thyroid carcinoma according to basal calcitonin level. J Clin Endocrinol Metab 90 (4): 2029-34, 2005. [PUBMED Abstract]
  198. Machens A, Lorenz K, Dralle H: Individualization of lymph node dissection in RET (rearranged during transfection) carriers at risk for medullary thyroid cancer: value of pretherapeutic calcitonin levels. Ann Surg 250 (2): 305-10, 2009. [PUBMED Abstract]
  199. Franc S, Niccoli-Sire P, Cohen R, et al.: Complete surgical lymph node resection does not prevent authentic recurrences of medullary thyroid carcinoma. Clin Endocrinol (Oxf) 55 (3): 403-9, 2001. [PUBMED Abstract]
  200. van Heurn LW, Schaap C, Sie G, et al.: Predictive DNA testing for multiple endocrine neoplasia 2: a therapeutic challenge of prophylactic thyroidectomy in very young children. J Pediatr Surg 34 (4): 568-71, 1999. [PUBMED Abstract]
  201. Hansen HS, Torring H, Godballe C, et al.: Is thyroidectomy necessary in RET mutations carriers of the familial medullary thyroid carcinoma syndrome? Cancer 89 (4): 863-7, 2000. [PUBMED Abstract]
  202. Wells SA Jr, Donis-Keller H: Current perspectives on the diagnosis and management of patients with multiple endocrine neoplasia type 2 syndromes. Endocrinol Metab Clin North Am 23 (1): 215-28, 1994. [PUBMED Abstract]
  203. Gardet V, Gatta B, Simonnet G, et al.: Lessons from an unpleasant surprise: a biochemical strategy for the diagnosis of pheochromocytoma. J Hypertens 19 (6): 1029-35, 2001. [PUBMED Abstract]
  204. Pacak K, Ilias I, Adams KT, et al.: Biochemical diagnosis, localization and management of pheochromocytoma: focus on multiple endocrine neoplasia type 2 in relation to other hereditary syndromes and sporadic forms of the tumour. J Intern Med 257 (1): 60-8, 2005. [PUBMED Abstract]
  205. Raue F, Kraimps JL, Dralle H, et al.: Primary hyperparathyroidism in multiple endocrine neoplasia type 2A. J Intern Med 238 (4): 369-73, 1995. [PUBMED Abstract]
  206. Milos IN, Frank-Raue K, Wohllk N, et al.: Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation. Endocr Relat Cancer 15 (4): 1035-41, 2008. [PUBMED Abstract]
  207. Marsh DJ, McDowall D, Hyland VJ, et al.: The identification of false positive responses to the pentagastrin stimulation test in RET mutation negative members of MEN 2A families. Clin Endocrinol (Oxf) 44 (2): 213-20, 1996. [PUBMED Abstract]
  208. Mandel SJ, Brent GA, Larsen PR: Levothyroxine therapy in patients with thyroid disease. Ann Intern Med 119 (6): 492-502, 1993. [PUBMED Abstract]
  209. Sawin CT, Geller A, Hershman JM, et al.: The aging thyroid. The use of thyroid hormone in older persons. JAMA 261 (18): 2653-5, 1989. [PUBMED Abstract]
  210. Baloch Z, Carayon P, Conte-Devolx B, et al.: Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 13 (1): 3-126, 2003. [PUBMED Abstract]
  211. Samaan NA, Schultz PN, Hickey RC: Medullary thyroid carcinoma: prognosis of familial versus nonfamilial disease and the role of radiotherapy. Horm Metab Res Suppl 21: 21-5, 1989. [PUBMED Abstract]
  212. Scherübl H, Raue F, Ziegler R: Combination chemotherapy of advanced medullary and differentiated thyroid cancer. Phase II study. J Cancer Res Clin Oncol 116 (1): 21-3, 1990. [PUBMED Abstract]
  213. Cohen EE, Rosen LS, Vokes EE, et al.: Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study. J Clin Oncol 26 (29): 4708-13, 2008. [PUBMED Abstract]
  214. Lam ET, Ringel MD, Kloos RT, et al.: Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol 28 (14): 2323-30, 2010. [PUBMED Abstract]
  215. Carr LL, Mankoff DA, Goulart BH, et al.: Phase II study of daily sunitinib in FDG-PET-positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin Cancer Res 16 (21): 5260-8, 2010. [PUBMED Abstract]
  216. Kurzrock R, Sherman SI, Ball DW, et al.: Activity of XL184 (Cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol 29 (19): 2660-6, 2011. [PUBMED Abstract]
  217. Wells SA Jr, Robinson BG, Gagel RF, et al.: Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 30 (2): 134-41, 2012. [PUBMED Abstract]
  218. Fox E, Widemann BC, Chuk MK, et al.: Vandetanib in children and adolescents with multiple endocrine neoplasia type 2B associated medullary thyroid carcinoma. Clin Cancer Res 19 (15): 4239-48, 2013. [PUBMED Abstract]
  219. Walz MK, Alesina PF, Wenger FA, et al.: Posterior retroperitoneoscopic adrenalectomy--results of 560 procedures in 520 patients. Surgery 140 (6): 943-8; discussion 948-50, 2006. [PUBMED Abstract]
  220. Walz MK, Alesina PF, Wenger FA, et al.: Laparoscopic and retroperitoneoscopic treatment of pheochromocytomas and retroperitoneal paragangliomas: results of 161 tumors in 126 patients. World J Surg 30 (5): 899-908, 2006. [PUBMED Abstract]
  221. Lairmore TC, Ball DW, Baylin SB, et al.: Management of pheochromocytomas in patients with multiple endocrine neoplasia type 2 syndromes. Ann Surg 217 (6): 595-601; discussion 601-3, 1993. [PUBMED Abstract]
  222. Okamoto T, Obara T, Ito Y, et al.: Bilateral adrenalectomy with autotransplantation of adrenocortical tissue or unilateral adrenalectomy: treatment options for pheochromocytomas in multiple endocrine neoplasia type 2A. Endocr J 43 (2): 169-75, 1996. [PUBMED Abstract]
  223. Inabnet WB, Caragliano P, Pertsemlidis D: Pheochromocytoma: inherited associations, bilaterality, and cortex preservation. Surgery 128 (6): 1007-11;discussion 1011-2, 2000. [PUBMED Abstract]
  224. Scholten A, Valk GD, Ulfman D, et al.: Unilateral subtotal adrenalectomy for pheochromocytoma in multiple endocrine neoplasia type 2 patients: a feasible surgical strategy. Ann Surg 254 (6): 1022-7, 2011. [PUBMED Abstract]
  225. Grubbs EG, Rich TA, Ng C, et al.: Long-term outcomes of surgical treatment for hereditary pheochromocytoma. J Am Coll Surg 216 (2): 280-9, 2013. [PUBMED Abstract]
  226. Norton JA, Brennan MF, Wells SA Jr: Surgical Management of Hyperparathyroidism. In: Bilezikian JP, Marcus R, Levine MA: The Parathyroids: Basic and Clinical Concepts. New York: Raven Press, 1994, pp 531-551.
  227. Khan MI, Waguespack SG, Hu MI: Medical management of postsurgical hypoparathyroidism. Endocr Pract 17 (Suppl 1): 18-25, 2011 Mar-Apr. [PUBMED Abstract]
  228. Stålberg P, Carling T: Familial parathyroid tumors: diagnosis and management. World J Surg 33 (11): 2234-43, 2009. [PUBMED Abstract]
  229. Peacock M, Bilezikian JP, Klassen PS, et al.: Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab 90 (1): 135-41, 2005. [PUBMED Abstract]
  230. Schuffenecker I, Ginet N, Goldgar D, et al.: Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma. Le Groupe d'Etude des Tumeurs a Calcitonine. Am J Hum Genet 60 (1): 233-7, 1997. [PUBMED Abstract]
  231. Norum RA, Lafreniere RG, O'Neal LW, et al.: Linkage of the multiple endocrine neoplasia type 2B gene (MEN2B) to chromosome 10 markers linked to MEN2A. Genomics 8 (2): 313-7, 1990. [PUBMED Abstract]
  232. Carlson KM, Bracamontes J, Jackson CE, et al.: Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet 55 (6): 1076-82, 1994. [PUBMED Abstract]
  233. Kitamura Y, Scavarda N, Wells SA Jr, et al.: Two maternally derived missense mutations in the tyrosine kinase domain of the RET protooncogene in a patient with de novo MEN 2B. Hum Mol Genet 4 (10): 1987-8, 1995. [PUBMED Abstract]
  234. Freyer G, Ligneau B, Schlumberger M, et al.: Quality of life in patients at risk of medullary thyroid carcinoma and followed by a comprehensive medical network: trends for future evaluations. Ann Oncol 12 (10): 1461-5, 2001. [PUBMED Abstract]
  235. Freyer G, Dazord A, Schlumberger M, et al.: Psychosocial impact of genetic testing in familial medullary-thyroid carcinoma: a multicentric pilot-evaluation. Ann Oncol 10 (1): 87-95, 1999. [PUBMED Abstract]
  236. Grosfeld FJ, Lips CJ, Ten Kroode HF, et al.: Psychosocial consequences of DNA analysis for MEN type 2. Oncology (Huntingt) 10 (2): 141-6; discussion 146, 152, 157, 1996. [PUBMED Abstract]
  237. Johnston LB, Chew SL, Trainer PJ, et al.: Screening children at risk of developing inherited endocrine neoplasia syndromes. Clin Endocrinol (Oxf) 52 (2): 127-36, 2000. [PUBMED Abstract]
  238. MacDonald DJ, Lessick M: Hereditary cancers in children and ethical and psychosocial implications. J Pediatr Nurs 15 (4): 217-25, 2000. [PUBMED Abstract]
  239. Grosfeld FJ, Lips CJ, Beemer FA, et al.: Psychological risks of genetically testing children for a hereditary cancer syndrome. Patient Educ Couns 32 (1-2): 63-7, 1997 Sep-Oct. [PUBMED Abstract]
  240. Giarelli E: Multiple endocrine neoplasia type 2a (MEN2a): a call for psycho-social research. Psychooncology 11 (1): 59-73, 2002 Jan-Feb. [PUBMED Abstract]
  241. Grosfeld FJ, Lips CJ, Beemer FA, et al.: Distress in MEN 2 family members and partners prior to DNA test disclosure. Multiple endocrine neoplasia type 2. Am J Med Genet 91 (1): 1-7, 2000. [PUBMED Abstract]
  242. Grosfeld FJ, Beemer FA, Lips CJ, et al.: Parents' responses to disclosure of genetic test results of their children. Am J Med Genet 94 (4): 316-23, 2000. [PUBMED Abstract]
  243. Giarelli E: Bringing threat to the fore: participating in lifelong surveillance for genetic risk of cancer. Oncol Nurs Forum 30 (6): 945-55, 2003 Nov-Dec. [PUBMED Abstract]
  244. Schultz PN: Providing information to patients with a rare cancer: using Internet discussion forums to address the needs of patients with medullary thyroid carcinoma. Clin J Oncol Nurs 6 (4): 219-22, 2002 Jul-Aug. [PUBMED Abstract]
  • Updated: December 4, 2014